/ 


THE  LIBRARY 

OF 

THE  UNIVERSITY 
OF  CALIFORNIA 

PRESENTED  BY 

PROF.  CHARLES  A.  KOFOID  AND 
MRS.  PRUDENCE  W.  KOFOID 


fit 


ON  THE 


ANTAGONISM 


BETWEEN  MEDICINES 


AND 


BETWEEN  REMEDIES  AND  DISEASES. 


BEING 


THE    CARTWRIGHT  LECTURES  FOR    THE    TEAR    1880. 


BY 

EOBEETS  BAKTJEOLOW,  M.A.,  M.  D.,  LL.  D., 

PROFESSOR    OF    MATERIA    MEDICA    AND    GENERAL    THERAPEUTICS    IN    THE    JEFFERSON    MEDIOJLL 

COLLEGE  OF  PHILADELPHIA  J  FELLOW  OF  THE  COLLEGE  OF  PHYSICIANS  OF  PHILADELPHIA ; 

MEMBER    OF     THE     AMERICAN    PHILOSOPHICAL    SOCIETY  \     PRESIDENT    OF     THE 

AMERICAN  NEUROLOGICAL  ASSOCIATION  ;    AUTHOR    OF  A  "  TREATISE  ON 

MATERIA    MEDICA    AND    THERAPEUTICS,"    AND  A   "TREATISE 

ON  THB  PRACTICE  OF    MEDICINE,"  ETC. 


NEW    YOKE: 
D.     APPLETON    AND    COMPANY, 

1,   3,   AND    5   BOND    STREET. 
1881. 


COPYRIGHT  BT 

D.  APPLETON  AND  COMPANY, 

1881. 


B'* 


TO 
DBS.  W.  H.  DRAPER  AND  ROBERT  F.  WEIR, 

LATE   AND   PRESENT   PRESIDENTS    OF   THE    ALUMNI   ASSOCIATION    OF   THE 
COLLEGE    OF   PHYSICIANS   AND   SURGEONS,  NEW  YORE, 

jn8  Wunte, 

APPEECIATION   OF   THAT   HONEST  WOEK   WHICH   HAS   ADVANCED 

THEM   TO   THE   FEONT   BANK   OF   PBAOTITIONEES, 

IN  TESTIMONY   OF  MY   ESTEEM  FOE   THEM  PEESONALLY, 

AND   IN   GEATEFUL  EECOGNITION    OF 

PEBSONAL  KINDNESSES. 


• -'345846 


PEEFAOE. 


THE  Lectures  which  now  appear  in  this  form  owe  their  exist- 
ence to  the  well-directed  liberality  of  the  late  Mr.  Cartwright,  of 
Newark,  'New  Jersey.  On  the  opening  night  of  the  course,  Dr. 
"Weir,  President  of  the  Alumni  Association  of  the  College  of  Physi- 
cians and  Surgeons,  in  an  introductory  address,  gave  an  interesting 
account  of  the  circumstances  under  which  the  Cartwright . Lectures 
originated.  The  bequest  of  Mr.  Cartwright,  made  to  the  Alumni 
Association,  provides  for  an  annual  course  of  lectures  and  a  prize 
essay.  A  committee  of  the  Association,  appointed  to  select  a 
lecturer  to  inaugurate  the  course,  kindly  nominated  me ;  and  they 
designated  five  or  six  as  the  number  of  lectures  to  be  delivered, 
leaving  to  the  lecturer  the  selection  of  the  topic.  Not  to  estab- 
lish a  precedent  which  might  be  construed  to  favor  the  minimum 
number,  I  delivered  six  lectures.  The  topic  selected  is  one  to 
which  I  have  given  much  consideration  and  considerable  experi- 
mental work,  and  is,  I  think,  of  importance  to  the  profession. 
Although  the  literature  of  the  subject  is  extensive,  the  papers 
referring  to  it  are  widely  distributed  through  the  medical  periodi- 
cals of  various  countries.  To  this  statement  I  must  except  the 
prize  essay  of  Dr.  Fothergill,*  which  contains  an  interesting  dis- 
cussion of  the  topics  embraced  in  these  lectures.  I  should  also 

*  "  The  Antagonism  of  Therapeutical  Agents ;  and  What  it  Teaches,"  the  essay 
to  which  was  awarded  the  Fothergillian  Gold  Medal  of  the  Medical  Society  of  London 
for  1878.  By  J.  Milner  Fothergill,  M.  D.,  Edin.,  etc.  Philadelphia:  H.  C.  Lea,  1878. 
Pp.  160. 


<  PEEFAOE. 

except  some  of  the  monographs,  referred  to  in  the  course  of  the 
lectures,  but  most  of  these  are  not  accessible  to  the  great  body  of 
practitioners.  I  have  attempted  to  collect  here  all  of  the  contri- 
butions to  the  subject,  and  at  the  same  time  have  brought  forward 
my  own  work  in  this  field.  From  these  materials  I  have  sought 
to  develop  a  therapeutical  system,  which,  while  the  oldest,  is  at  the 
same  time  the  newest  phase  in  the  treatment  of  disease. 

An  abstract  of  these  lectures  appeared,  as  they  were  delivered, 
in  the  "  Medical  Record,"  and  they  were  published  in  full  in  the 
"  K"ew  York  Medical  Journal "  for  January  and  February,  1881. 
Their  appearance  in  this  volume  is  in  deference  to  the  judgment 
of  those  who  supposed  their  preservation  in  a  permanent  form 

desirable. 

B.  B. 

PHILADELPHIA,  February  1,  1881. 


TABLE   OF  CONTENTS. 


LECTURE  I. 

PAGE 

INTRODUCTORY   .            .            .            .            .            .            .            .  .      9 

HISTORY  OF  THE  SUBJECT    .......  10 

PHYSICAL  BASIS  OF  THE  PRINCIPLE       .            .            .                       .  .20 

OPIUM  AND  BELLADONNA    .......  22 

LECTURE  II. 

OPIUM  AND  BELLADONNA,  CONTINUED       .        .            .            .            .  .31 

LECTURE  III. 

ATEOPIA  AND  PHYSOSTIGMA            ......  49 

ATROPIA  AND  PILOOARPIN         .            .            .                       .            .  .57 

ATROPIA  AND  MUSCARIA      .......  61 

ATROPIA  AND  QUINIA    .            .            .            .            .                        .  .64 

ATROPIA  AND  BROMAL  HYDRATE    ......  64 

ATROPIA  AND  ACONITE  .            .            .            .            .            .            .  .65 

LECTURE  IV. 

CHLORAL  AND  STRYCHNIA    .......  67 

CHLORAL  AND  PIOROTOXINE,      .            .            .            .            .            .  .71 

CHLORAL  AND  ATROPIA       .......  72 

ANTAGONISTS  TO  THE  CARDIAC  AND  RESPIRATORY  DEPRESSANTS         .  .    74 

•OPIUM  AND  VERATRUM  YIRIDE       ......  74 

OPIUM  AND  GELSEMIUM         .  ......    77 

MORPHIA  AND  THEINE,  CAFFEINE,  ETC.       .....  79 

MORPHIA  AND  CHLOROFORM      .            .            .            .            .            .  .79 

STRYCHNIA  AS  A  RESPIRATORY  STIMULANT             ....  81 

STRYCHNIA  AND  NITRITE  OF  AMYL        .            .            .            .           .  .82 

ACONITE  AND  DIGITALIS      .......  82 

DlGITALIN  AND  SAPONIN           .            .            .            .            .           .  .83 

DlGITALIN  AND  MuSOARIA     .......  83 

ATROPIA  AND  PHYTOLAOOA       .            .           '.            .            .            .  .84 

ANAESTHETICS  AND  CONVULSANTS  85 


8  TABLE    OF    CONTENTS. 

LECTURE  V. 

PAGE 

THE  ANTAGONISM  BETWEEN  KEMEDIES  AND  DISEASES   .            .            .  .86 

STRYCHNIA  AND  PAEALYTIO  STATES            .....  86 

SPASM  AND  THE  PAEALYZEES    .            .            .            .            .            .  .88 

PAIN  AND  THE  ANODYNES    .......  92 

MENTAL  STATES  AND  THEIR  ANTAGONISTS         .            .            .            .  .94 

CARDIAC  REMEDIES  AND  DISEASES  .            .            .            .            .  95 

RESPIRATION  REMEDIES  AND  DISEASES  .            .            .            .            .  .98 

INTESTINAL  REMEDIES  AND  DISEASES           .            .            .            .  .           99 

REMEDIES  ACTING  ON  THE  SKIN             .            .            .            .            .  .99 

REMEDIES  ACTING  ON  THE  KIDNEYS  AND  BLADDER              .            .  .100 

LECTURE  VI. 

ANTAGONISM  BETWEEN  REMEDIES  AND  DISEASES           .            .            .  .102 

ANTAGONISTS  TO  INFLAMMATION     .            .            .            .            .  .102 

ANTAGONISTS  TO  FEVER             .            .            .            .            .            .  .106 

ANTAGONISTS  TO  SPECIFIC  DISEASES            .            .            .            .  .111 

APPENDIX .115 

INDEX                                                                                             .  .         120 


,  THE 

ANTAGONISM  BETWEEN  MEDICINES, 


AND  BETWEEN 


REMEDIES  AND  DISEASES. 


LECTUEE  I. 

HISTORY   OF   THE   SUBJECT ;    PHYSICAL  BASIS  OF    THE    PRINCIPLE ;    OPIUM 

AND  BELLADONNA. 

IN  this  country,  private  beneficence,  although  vast  in  the  extent 
of  its  exercise,  is  rarely  directed  to  merely  medical  objects.  There- 
fore, in  opening  this  course  of  lectures,  provided  for  under  the  be- 
quest of  the  late  Mr.  Cartwright,  it  behooves  us  to  honor  the  memory 
of  the  founder.  In  this  gift,  precious  indeed  on  account  of  its  rar- 
ity, the  medical  profession  is  offered  a  new  opportunity,  when  such 
opportunities  are  few,  for  honorable  distinction.  The  possibilities 
of  this  benefaction  are  great.  The  opportunity  stimulates  to  the 
acquisition  of  new  truths,  and  encourages  the  growth  of  a  medical 
literature.  Benefits  inure  to  the  memory  of  the  giver.  His  name 
is  perpetuated  among  the  alumni  of  this  great  school,  and  they  have 
it  in  charge  to  honor  through  all  time.  His  benefaction  is  espe- 
cially celebrated  annually,  and  he  is  enrolled  among  the  philanthro- 
pists who,  by  a  wise  dispensation  of  their  wealth,  have  sought  to 
promote  the  good  of  their  fellow-men. 

I  esteem  it  a  high  honor  to  be  called  upon  to  inaugurate  the 


10  DEFINITION. 

Cartwright  Lectures,  and  I  am  deeply  indebted  to  the  Committee 
for  the  kind  partiality  which  led  them  to  nominate  me.  I  do  not 
conceal  from  myself  the  difficulties  of  this  position.  The  Cartwright 
Lectures  will  be  expected  to  take  and  maintain  an  honorable  position 
alongside  of  the  Gulstonian,  Lumleian,  and  other  lecture  courses, 
which  have  done  so  much  for  English  medical  science  and  literature. 
It  will  doubtless  be  expected  of  the  lecturers  to  bring  forward  new 
facts,  to  develop  new  principles,  and  to  throw  new  light  on  obscure 
but  familiar  topics.  Brought  into  comparison  with  such  standards, 
and  confronted  with  the  just  expectations  of  the  profession,  it  is  but 
natural  to  apprehend  that  my  effort  will  fall  far  short  of  a  true  ideal, 
and  unhappily  become  a  precedent  for  inferior  performances  in  the 
future.  After  careful  consideration,  I  have  selected  a  topic  for  this 
course  which  has  strong  claims  on  the  attention  of  physicians,  and 
to  which  I  have  contributed  some  facts  by  recent  researches.  Ac- 
cordingly, I  have  decided  to  ask  your  attention  to  the  subject  of  the 
Antagonism  between  Medicines,  and  between  Remedies  and  Dis- 
eases. 

By  physiological  antagonism  is  meant  a  balance  of  opposed  ac- 
tions on  particular  organs  or  tissues.  As  disease  is  a  pathological 
physiology,  so  far,  at  least,  as  relates  to  function,  the  derangements 
produced  by  disease  may  be  opposed  by  other  derangements  set  up 
by  medicinal  substances.  The  antagonism,  or  opposition  of  actions, 
may  extend  throughout  the  whole  range  of  effects,  or  it  may  be 
limited  to  a  few  points.  Indeed,  some  of  the  most  valuable  in- 
stances of  antagonism  are  thus  limited,  and  there  are  few,  if  any,  ex- 
amples of  antagonism,  in  which  the  opposition  of  actions  is  universal. 
In  popular  medical  opinion,  by  the  term  physiological  antagonism 
is  meant  an  opposition  of  action  of  poisonous  medicinal  agents,  in 
that  the  effects  of  the  one  may  be  exactly  counterbalanced  by  the 
effects  of  the  other.  According  to  this  conception  of  the  subject, 
when  a  lethal  dose  of  one  agent  is  administered,  the  effects  may  be 
removed  by  an  opposing  agent  so  given  as  to  produce  exactly  oppo- 
site effects.  Therefore,  the  poisonous  action  ceases,  because  in  the 
whole  range  of  the  effects  of  the  two  agents  they  are  exactly  an- 
tagonized. This  conception  of  physiological  antagonism  is  exagger- 
ated —  for  such  completeness  of  opposing  action  is  as  rare  as  exact 
similitude  in  remedies  acting  in  the  same  way. 

In  an  interesting  discussion  *  of  the  problem  of  therapeutical 


*«Bull.  G4n.  de  Th6rap.,"  vol.  Ixxxiv,  p.  570.    . 


HISTORY.  11 

•antagonism,  MM.  Gubler  and  Labbee  proposed  to  retain  the  word 
antidotism  in  accordance  with  its  ancient  signification.  As,  how- 
ever, usage  has  restricted  the  employment  of  the  word  antidote  to 
express  chemical  rather  than  physiological  antagonism,  it  is  better 
to  adhere  to  the  present  nomenclature.  Moreover,  the  word  anti- 
dotism expresses  the  conception  of  a  chemical  combination  of  the 
opposing  agents,  and  the  formation  of  a  new  compound  different  in 
character  from  those  entering  into  its  composition,  and  without  toxic 
power.  Physiological  antagonism  means  simply  a  balance  of  op- 
posed actions  on  the  same  tissue.  It  does  not  include  a  change  of 
structure.  The  opposing  agents  counterbalancing  each  other,  the 
functional  disturbance  subsides  and  the  normal  equilibrium  is  re- 
stored. 

Some  such  conception  as  our  modern  doctrine  of  physiological 
antagonism  has  existed  from  the  earliest  period.  Various  aphorisms 
of  Hippocrates  express  it  in  most  precise  terms.  Thus :  "  Diseases 
which  arise  by  repletion  are  cured  by  depletion  ;  and  those  which 
come  from  depletion  are  cured  by  repletion,  and  in  general  diseases 
are  cured  by  their  contraries."  In  another  aphorism  it  is  stated : 
'"Some  diseases  are  cured  by  contraries,  some  by  similars" — an 
aphorism  on  which  Carus  based  his  famous  saying,  in  his  controversy 
with  Hahnemann  :  "  Whatever  is  new  in  homoeopathy  is  not  true, 
and  what  is  true  is  not  new."  Although  the  practice  of  Hip- 
pocrates and  his  immediate  followers  was  empirical,  that  is,  based 
on  observation  and  experience,  they  used,  whenever  the  circum- 
stances admitted,  their  favorite  dogma  of  contraries.  Some  of  the 
most  famous  teachers  of  the  Alexandrian  school — for  example,  He- 
rophilus  and  Eristratus — opposed  the  doctrine  of  contraries.  Galen 
was  essentially  a  trimmer,  for,  while  he  practiced  on  the  system  of 
contraries,  he  spoke  respectfully  of  the  empiricists.  There  has  been 
no  period  in  medical  annals  when  theories,  and  systems,  and  special- 
isms of  all  kinds  were  more  numerous  and  distracting  than  in  Galen's 
time.  The  only  rational  expedient  applicable  to  medical  practice 
at  that  time  was  the  principle  of  contraries,  which  continued  up  to 
the  revival  of  learning  as  the  chief  guide  in  therapeutics,  how  much 
soever  other  theories  may  have  dominated  in  the  schools. 

About  the  middle  of  the  sixteenth  century,  there  was  published 
by  Jean  Fernel,  physician  to  Henry  II,  teacher  of  Yesalius,  and  the 
most  celebrated  physician  of  his  time,  an  elaborate  treatise  on  the 
iundamental  maxim,  "  Every  disease  must  be  combated  by  contrary 
remedies."  It  is  a  curious  circumstance  that  Fernel  should  attempt 


12  HISTORY. 

to  prove  that  the  law  or  doctrine  of  similars  was  only  an  application 
of  its  opposite  or  law  of  contraries.  "  Many  men,"  he  states,  "  con- 
ceive that  this  sovereign  principle  is  annulled  when  it  is  affirmed  that 
there  are  diseases  which  are  cured  by  similars ;  but  these  persons  do 
not  reflect  that  such  remedies,  although  apparently  similar  in  their 
effects  to  the  symptoms  of  the  disease,  are  opposed  to  the  causes 
which  produced  it,  so  that  they  destroy  the  disease  by  removing  its 
cause ;  thus  rhubarb,  though  heating,  extinguishes  fever  by  purging 
the  matter  which  feeds  the  fire.  A  purgative  arrests  a  dysentery  by 
evacuating  the  peccant  matter  which  causes  and  sustains  it."  The 
ingenious  attempt  of  Fernel  could  not  prevent  the  decline  of  the 
ancient  doctrines,  which  had  maintained  universal  sway  for  so  many 
centuries.  When  that  boasting  pretender  and  iconoclast,  Paracel- 
sus, burned  the  works  of  Galen  and  Avicenna,  the  doctrine  of  con- 
traries disappeared  in  the  smoke.  On  the  labors  of  the  alchemists 
rose  modern  chemistry.  "With  the  new  light  afforded  by  the  dis- 
covery of  the  circulation  of  the  blood,  and  the  progress  of  the  knowl- 
edge of  anatomy,  new  theories  prevailed  in  therapeutics.  The  iatro- 
chemical  doctrine  of  the  great  Boerhaave,  the  animus  of  Stahl,  the 
irritability  of  Cullen,  and  the  sthenic  and  asthenic  theories  of  Brown, 
for  a  time  held  sway  within  the  range  of  influence  of  their  respec- 
tive authors. 

The  doctrine  of  contraries,  then,  quite  disappeared  amid  the 
contentions  of  rival  schools  and  professors.  Next  arose  that  eccen- 
tric and  mystical  reformer,  Hahnemann,  near  the  close  of  the  last 
cenhiry,  whose  notions,  tinctured  with  the  spiriticism  of  Mesmer, 
were  rendered  still  more  visionary  by  the  radical  theories  engendered 
by  the  French  Eevolution.  Before  that  period,  in  his  senility, 
when  he  developed  his  idea  of  the  spiritual  essence  in  medicine, 
Hahnemann's  doctrine  of  similars  was  merely  an  application  of  the 
Hippocratic  maxim.  The  law  of  similars  was  associated  with  the 
law  of  contraries  in  the  Hippocratic  system,  and  Fernel,  in  the  six- 
teenth century,  in  expounding  and  defending  the  latter,  showed  its 
relation  to  the  former.  A  little  consideration  must,  I  think,  tend 
to  the  conclusion  that,  when  a  remedy  acts  in  a  similar  manner  to 
a  disease,  there  must  be  an  antagonism  between  the  force  of  the 
remedy  and  the  momentum  acquired  by  the  disease.  The  disturb- 
ance in  the  functions  caused  by  a  drug  must  interfere  with  the  dis- 
turbance caused  by  a  morbid  process.  If  the  actions  were  the  same, 
the  result  of  the  combined  impression  would  be  an  increase  of  the 
disturbance.  As  they  are  similar  only,  and  proceed  from  different 


HISTORY.  13 

-sources,  there  are,  then,  two  forces  acting  on  the  same  tissue  or 
organs,  and  necessarily  opposed  in  action.  Any  truth  in  the  homoeo- 
pathic law  or  doctrine  of  similars  is  not,  therefore,  new,  as  Cams 
well  said,  for,  if  there  be  similarity  of  action,  it  must  of  necessity 
be  opposition. 

The  initial  movement  in  the  great  development  which  has  taken 
place  in  our  knowledge  of  the  physiological  action  of  drugs  was  be- 
gun by  Bichat.  I  can  not  too  strongly  insist  on  the  importance  of 
this  epoch  for  a  right  understanding  of  the  influences  contributing 
to  this  development.  When  Bichat  came  on  the  scene,  therapeu- 
tics was  in  an  utterly  chaotic  state.  To  the  previously  existing  wild 
theories  of  the  iatro-chemists,  the  animists,  and  the  contra-stimulant 
school,  were  added  the  vagaries  of  Hahnemann  and  of  Mesmer.  It 
is  not  surprising  that  he  expresses  a  severe  judgment:  "Materia 
medica,"  says  Bichat,  "  a  collection  of  incoherent  opinions,  is  per- 
haps, of  all  the  physiological  sciences,  that  which  most  exhibits  the 
contradictions  of  the  human  mind.  In  fact,  it  is  not  a  science  for 
a  trained  intellect ;  it  is  a  shapeless  mass  of  inexact  ideas,  of  obser- 
vations often  puerile,  of  imaginary  remedies,  strangely  conceived 
.and  fantastically  arranged.  It  is  said  that  the  practice  of  medi- 
cine is  repulsive.  I  go  further  than  this  :  it  is,  in  respect  to  its  prin- 
.ciples  taken  from  our  materia  medicas,  impracticable  for  a  sensible 
man."  From  Bichat  dates  modern  physiology,  for,  although  great 
acquisitions  had  been  achieved  before,  it  was  not  until  he  rendered 
general  anatomy  *  possible  that  this  science  could  proceed  in  the 
.remarkable  course  of  development  which  has  since  taken  place. 
Here  is  the  initial  period  in  the  rise  of  experimental  physiology. 
Bichat  died  in  1802.  Magendie  was  then  passing  through  his 
course  of  study,  and,  brought  under  the  influence  of  Bichat,  was 
thoroughly  indoctrinated  with  the  ideas  of  that  brilliant  genius. 
Demonstrator  of  anatomy  in  1805,  a  few  years  later  (1808-'9)  his 
important  researches  on  physiological  subjects  began  to  appear.  The 
first  investigation  by  physiological  methods  into  the  action  of  a  med- 
icine was  made  by  Magendie,  the  subject  being  the  upas  poison. 
This  research  became  possible  only  after  the  functions  of  the  spinal 
nerves  had  been  correctly  interpreted — a  feat  accomplished  a  short 
time  before  by  Magendie.  He  next  investigated  the  then  new  alka- 
loid, strychnia,  and  so  successfully  did  he  work  out  all  the  details 

*  "  Anatoraie  Generate,  preced6e  des  Recherches  Physiologiques  sur  la  Vie  et  la  Mort," 
par  Xavier  Bichat,  Paris,  1818.     Two  volumes,  with  a  portrait. 


14  HISTORY. 

that  subsequent  experimentalists  have  been  able  to  add  but  little  to 
his  results.  The  first  example  of  the  physiological  antagonism  be- 
tween a  remedy  and  a  diseased  state  was  that  between  strychnia 
and  paralysis,  and  this  principle,  based  on  Magendie's  studies,  was 
applied,  not  empirically,  but  with  a  conscious  purpose,  by  a  physi- 
cian, after  the  publication  of  the  great  physiologist's  results.  I  am  the 
more  explicit  in  stating  this  fact,  because  it  is  generally  supposed 
that  the  employment  of  strychnia  in  these  maladies  was  merely  em- 
pirical or  accidental.  The  physiological  study  of  the  actions  of 
medicines  has  gone  on  actively  since  Magendie's  time,  but  the  ques- 
tion of  physiological  antagonism  has  not  excited  inquiry  until  within 
a  few  years  past.  The  doctrine  of  contraries,  without  being  dis- 
tinctly formulated  in  men's  minds,  influenced  therapeutics  to  a 
greater  or  less  extent.  The  scientific  application  of  the  principle  of 
antagonism  to  medical  practice,  I  purpose  to  consider  in  detail  in 
future  lectures. 

Taking  up  now  for  examination  the  special  instances  of  antag- 
onism between  medicines,  we  find,  so  long  ago  as  1570,  Pena  and 
De  Lobel  relating  that  the  overaction  of  belladonna,  when  given  to 
allay  thirst,  was  relieved  by  theriaca.  Prosper,  according  to  Giaco- 
mini,  held  that  theriaca  was  an  antidote  to  all  poisons.  Horatius, 
in  1661,  states  that  a  man  poisoned  by  a  teaspoonful  of  belladonna 
juice  recovered  after  taking  theriaca.  In  1677  Faber  narrated  sev- 
eral cases  of  poisoning  by  belladonna  berries,  in  which  theriaca  was 
partly  successful.  It  is  probable  that  theriaca  was  reputed  to  be 
an  antidote  to  the  poisons  in  general  at  this  period,  and  was  used  in 
belladonna  poisoning  as  in  other  forms  of  poisoning,  but  further  ob- 
servation demonstrated  that  it  was  especially  adapted  to  belladonna 
poisoning.  By  the  year  1810  considerable  experience  of  an  empirical 
kind  had  accumulated  in  regard  to  the  antagonism  of  opium  and 
belladonna  ;  for  we  find  that  in  this  year  Joseph  Lipp  published  an 
inaugural  thesis  on  the  toxic  effects  of  belladonna  berries,  and  on 
the  curative  powers  of  opium.  We  owe  to  Graves,  the  great  Dub- 
lin clinician,  the  first  really  scientific  suggestion  of  an  antagonism. 
He  supposed  that  the  state  of  the  pupil  would  afford  an  indica- 
tion in  fevers  of  the  need  of  opium  or  belladonna — the  former  to  be 
given  when  the  pupil  was  dilated,  the  latter  when  it  was  contract- 
ed. Acting  on  this  suggestion,  Dr.  Thomas  Anderson,*  of  Edin- 
burgh, employed  belladonna  against  opium  poisoning — a  mydriatic/ 

*  Braithwaite's  "Retrospect,"  1865,  part  xxx,  p.  301. 


HISTOEY.  15 

against  a  myositic — with  success.  Two  years  subsequently,  Dr. 
William  H.  Mussey,*  of  Cincinnati,  seeing  the  account  of  Dr.  An- 
derson's cases,  tried  the  same  expedient  successfully  in  a  case  of 
attempted  suicide  with  laudanum.  In  July,  1859,  Mr.  Benjamin 
Bell,f  of  Edinburgh,  published  an  account  of  two  cases,  in  which 
symptoms  of  poisoning  produced  by  the  subcutaneous  injection  of 
atropia  were  removed  by  considerable  doses  of  morphia.  Influenced 
by  these  results  of  Mr.  Bell's,  in  December  of  the  same  year,  Mr. 
Seaton,J  of  Leeds,  treated  eight  cases  of  poisoning  by  belladonna 
berries  with  opium — seven  of  the  eight  cases  recovering.  In  Jan- 
uary, 1862,  Dr.  C.  C.  Lee,§  of  Philadelphia,  reported  two  cases,  one 
of  opium -poisoning  treated  by  belladonna,  and  one  of  belladonna 
poisoning  treated  by  opium,  the  result  a  success  in  each  case.  Dr. 
Lee  also  entered  into  some  detail  on  the  literature  of  the  subject,  re- 
ferring to  the  experiences  of  Anderson,  Mussey,  and  Seaton,  and  to 
the  adverse  experiments  of  Brown-Sequard.  During  the  same  year 
(1862),  the  most  important  paper  which  had  hitherto  been  published 
made  its  appearance  from  the  pen  of  Dr.  William  F.  !N"orris.||  In 
this  paper,  the  cases  illustrating  an  antagonism  of  action  between 
opium  and  belladonna,  which  had  been  previously  published,  were 
tabulated  ;  and  a  full  historical  account  of  the  subject,  from  which 
subsequent  writers  have  drawn  their  information,  and  to  which  I 
ana  much  indebted,  is  there  given.  In  1865  an  admirable  paper, 
based  on  clinical  and  experimental  observations  made  at  the  mili- 
tary hospital  for  wounds  and  injuries  of  the  nerves,  and  embody- 
ing the  results  of  an  immense  experience,  was  published  by  Drs. 
Mitchell,  Morehouse,  and  Keen.  Tf  In  the  following  year  (1866), 
Dr.  Constantin  Paul  **  published  a  monograph,  supporting  the  view 
of  the  existence  of  such  antagonism.  Since  this  time  the  cases,  pa- 
pers, and  monographs  have  so  greatly  multiplied  that  it  would  be 
impracticable  to  name  them  all  in  this  historical  review.  I  have 
collected  all  the  published  cases  for  statistical  study,  and  will  refer 
to  the  more  important  papers  and  monographs  hereafter.  The  cases 

*  "Cincinnati  Med.  Observer,"  vol.  i,  1856,  p.  70.     There  were  but  two  volumes  issued 
of  this  periodical,  when  it  was  united  with  the  "  Lancet." 

f  "Edinburgh  Med.  Jour.,"  vol.  iv,  1859,  p.  1. 

\  "Med.  Times  and  Gaz.,"  Dec.  3,  1859,  p.  551. 

§  "Am.  Jour,  of  the  Med.  Sci.,"  vol.  xlii.  ||  Ibid.,  vol.  xliv. 

"  f  "Am.  Jour,  of  the  Med.  Sci.,"  July,  1865,  vol.  1,  p.  67.  "On  the  Antagonism 
of  Atropia  and  Morphia.  Founded  on  Observations  and  Experiments  made  at  the  United 
States  Hospital  for  Injuries  and  Diseases  of  the  Nervous  System." 

**  "De  1'Antagonisme  en  Pathologie  et  en  The"rapeutique,"  1866.     Pp.  92-115. 


16  nfsTOEY. 

thus  far  published  number  one  hundred  and  twenty  of  opium  and 
belladonna  poisoning,  in  which  the  one  drug  was  used  to  counter- 
balance the  effects  of  the  other. 

The  history  of  this  subject  would  not  be  complete  without  some 
reference  to  the  opinions  of  those  who  doubt  the  existence  of  the 
antagonism,  or  disbelieve  in  it  utterly.  The  opposition  to  the  gen- 
erally accepted  view  is  based  chiefly  upon  researches  on  animals. 
The  most  influential  of  these  experimentalists  is  Brown-Sequard.* 
His  observations  have  been  made  for  the  most  part  on  guinea-pigs 
and  rabbits.  Bois  f  studied  the  effects  of  these  agents  on  cats.  He 
regards  the  following  experiments  as  conclusive  against  the  view 
that  an  antagonism  exists.  To  a  cat  he  gave  a  dose  of  morphia 
just  less  than  sufficient  to  cause  death;  when  entirely  recovered 
from  the  effects  of  this  quantity,  he  gave  to  the  same  cat  a  dose  of 
atropia  having  effects  just  short  of  lethal.  When  a  sufficient  time 
had  elapsed  to  insure  complete  recovery  from  that  dose,  he  adminis- 
tered those  quantities  together,  when  the  result  was  fatal.  Camus  f 
investigated  the  action  of  the  alkaloids  of  opium,  and  the  antago- 
nism of  atropia  and  morphia,  using  cats  and  pigeons,  while  Onsum  § 
conducted  his  researches  on  frogs.  In  what  mode  soever,  or  on  what 
animals,  the  investigations  were  conducted,  the  results  were  uni- 
formly opposed  to  the  existence  of  an  antagonism.  I  may  now  an- 
ticipate so  far  as  to  say  that  the  methods  of  investigation  pursued 
were  not  free  from  sources  of  fallacy,  and  that  the  results  obtained 
were  largely  vitiated.  The  most  elaborate  series  of  experiments  on 
this  topic,  embracing  animals  and  men,  were  those  of  HarleyJ  but 
his  facts  admit  of  a  different  interpretation  from  that  which  he  has 
given  them.  His  fundamental  error  consists  in  regarding  as  exam- 
ples of  antagonism  only  those  in  which  the  opposition  of  actions 
exists  throughout  the  whole  range  of  effects,  which,  as  I  have  already 
stated,  is  hardly  true  of  any  known  examples.  While  it  is  true  that 
clinical  experience  strongly  supports  the  belief  in  the  existence  of 
such  antagonism,  there  have  been  published  unsuccessful  cases. 

Although  opium  and  belladonna  were  the  first,  they  are  not  the 
only  examples  of  antagonistic  action.  In  fact,  we  find  that  more 
perfect  illustrations  of  antagonism  have  been  discovered  between 

*  "Jour,  de  la  Physiol.,"  etc.,  tome  iii,  1860,  p.  726. 

f  "  Gaz.  des  Hop.,"  71,  1865. 

J  "Gaz.  Hebdom.,"  2  se>.,  xii,  32,  1865. 

§  "  Schmidt's  Jahrbucher,"  Band  128,  p.  288,  abstract. 

fl  "  The  Old  Vegetable  Neurotics,"  p.  280,  and  p.  291. 


HISTORY.  17 

other  agents.     A  capital  example  of  a  remedy  being  applied  in  an- 
tagonism to  a  diseased  state  is  that  of  strychnia.     Magendie  under- 
took the  examination  of  the  properties  of  this  poison,  demonstrated 
its  mode  of  action  on  animals,  and  suggested  its  therapeutical  appli- 
cation in  opposition  to  certain  diseased  states.     When  Magendie's 
results  were  announced,  M.  Fouquier  applied  it  in  accordance  with 
the  deductions  of  experiment.    Magendie,  also,  when  the  opportunity 
offered,  used  the  agent  as  he  had  suggested  its  use,  in  the  following 
comprehensive  statement:  "Medicine  would,  perhaps,  derive  great 
advantage  from  the  knowledge  of  a  substance  whose  property  is  to 
act  on  the  spinal  cord,  for  we  know  that  many  severe  diseases  have 
their  seat  in  this  part  of  the  nervous  system."     Producing  tetanic 
rigidity,  the  opposite  condition  to  paralysis,  it  was  suggested  that 
it  might  prove  useful  in  paralysis.     I  need  not  say  that  this  sug- 
gestion was  abundantly  confirmed  by  clinical  experience,  and  since 
that  time  many  cases  have  demonstrated  the  correctness  of  the  an- 
tagonism.    Could  any  fact  more  strikingly  prove  the  benefits  de- 
rived from  the  physiological  study  of  the  action  of  remedies,  and  the 
applicability  of  the  law  or  principle  of  antagonism  to  therapeutics? 
In  the  remarkable  study  of  woorara  made  by  Bernard,  the  pupil  of 
Magendie,  we  have  another  illustration  of  the  same  fact.     Woorara 
is  a  paralyzer ;  it  destroys  the  irritability  of  the  end  organs  of  the 
nerves  in  the  muscles,  and  as  a  paralyzer  is  used  against  the  oppo- 
site condition,  or  spasm,  in  tetanus  and  in  hydrophobia.     In  respect 
to  the  latter  disease,  woorara  is  the  single  remedy  which  has  ap- 
peared to  have  a  curative  influence.     These  researches  of  Magendie 
and  Bernard  stand  out  prominently  in  medical  history  as  the  initia- 
tion of  that  course  of  physiological  study  of  remedies  which  has 
yielded  such  important  results,  and  ought  to  be  sufficient  in  them- 
eelves  to  silence  for  ever  the  absurd  cavils  of  the  antivivisectionists. 
Taking  the  examples   of    physiological    antagonism    in    their 
chronological   order,   the  next  one  is  that  between   atropia  and 
physostigma.     The  tirst  attempt  to  determine  the  existence  of  an 
antagonism,  which  had  been  suspected  previously,  was  by  Klein- 
wachter,*  in  1864,  who,  in  a  case  of  atropia  poisoning,  used  with 
distinct   advantage  a  preparation  of  physostigma.     The  next  ob- 
servation consisted    of  a   single   experiment   by  Bourneville,f   in 
which  the  effects  of  a  supposed  lethal  dose  of  Calabar  bean,  intro- 

*  "Berlin,  klin.  Woch.,"  1864,  p.  3,  369. 

f  "De  1'Emploi  de  la  Ffcve  de  Calabar  dans  le  Traitement  du  TStanos,"  Paris,  1867. 


18  HISTOEY. 

duced  into  the  stomach  of  an  animal,  were  counterbalanced  by 
the  subcutaneous  injection  of  atropia.  The  account  of  this  ex- 
periment did  not  appear  until  1867,  and  was  then  interpolated  in  a 
memoir  on  the  use  of  Calabar  bean  in  tetanus.  During  the  same 
year,  I  was  engaged  in  some  experimental  investigations  on  the 
actions  of  atropia,  and  on  its  antagonists,  with  a  view  to  the  prep- 
aration of  an  essay  to  be  offered  in  competition  for  the  annual 
prize  of  the  American  Medical  Association.  This  essay  appeared 
in  the  volume  of  "  Transactions  "  for  1869,  and  in  it  I  distinctly 
asserted  the  existence  of  the  antagonism,  and  submitted  experimen- 
tal evidence  in  its  support.  The  following  year,  the  remarkable 
paper  of  Professor  Thomas  R.  Fraser  *  appeared,  on  the  antagonism 
of  atropia  and  physostigma.  In  this  paper,  not  only  is  the  an- 
tagonism established,  and  its  limits  defined,  but  the  method 
pursued  is  so  admirable  as  to  remain  the  model  for  all  similar 
investigations. 

The  next  study  of  the  physiological  antagonism  of  remedies  is 
that  of  Professor  Preyer,  of  Jena,  the  first  part  of  whose  elabo- 
rate treatise  on  prussic  acid  appeared  in  1868.f  In  this,  and 
in  the  second  part  which  appeared  two  years  later,  Professor  Preyer 
maintained  that  the  actions  of  hydrocyanic  acid  and  of  atropia 
were  opposed,  especially  as  respects  the  effect  of  each  on  the  res- 
piratory function.  This  opinion  has  been  much  controverted  by 
Drs.  Lecorche  and  Meuriot,  J  of  Paris ;  Drs.  Hare  and  Keen,  §  of 
Philadelphia;  Professor  Schroff,  of  Vienna;  Professor  Boehm,||  of 
Dorpat;  and  myself. T  In  a  subsequent  paper,**  Professor  Preyer 
pays  his  respects  to  all  of  us  in  turn,  and  maintains  his  own  position 
with  fresh  arguments  and  illustrations. 

In  1869  MM.  Schmiedeberg  and  Koppe  isolated,  defined  the 
properties,  and  studied  the  antagonisms  of  muscarine,  the  alkaloid 
of  agaricus  muscarius.  They  conclude  that  the  effects  of  muscarine 

*  "  An  Experimental  Research  on  the  Antagonism  between  the  Actions  of  Physo- 
stigma and  Atropia."  From  the  "  Trans,  of  the  Royal  Soc.  of  Edinburgh,"  vol.  xxvi,  1872. 

|  "  Die  Blausaure  physiologisch  untersucht."    In  zwei  Theilen.    Bonn,  1868. 

\  "Arch.  Gen.  de  Med.,"  May,  1868,  p.  529. 

§  "  Am.  Jour,  of  the  Med.  Sci.,"  vol.  Iviii,  p.  436.  [Proc.  of  the  Path.  Soc.  of 
Phila.] 

|  "  Ueber  die  physiologischen  Wirkungen  der  Blausaure  und  den  angeblichen  An- 
tagonismus  von  Blausaure  und  Atropin."  "  Arch.  f.  experiment.  Pathol.  u.  Pbarmacol.," 
Band  ii,  p.  129. 

If  Prize  Essay. 

**"Die  Blausaure  physiologisch  untersucht,1'  Band  Hi,  p.  381. 


HISTOKY.  1 9 

are  similar  to  those  of  physostigma,  and  that  it  is  like  the  latter, 
also,  in  being  an  antagonist  to  atropia.  In  1869  the  remarkable 
memoir  of  Dr.  Oscar  Liebreich,  *  in  which  he  announced  the  dis- 
covery of  chloral,  appeared,  and  soon  after  the  same  author  de- 
monstrated the  antagonism  of  chloral  and  strychnia. 

A  notable  event,  in  connection  with  the  history  of  this  sub- 
ject, was  the  appointment  of  a  committee  by  the  British  Medical 
Association  "to  investigate  the  antagonism  of  medicines." f  The 
committee  was  composed  of  Dr.  J.  H.  Bennett,  the  great  Edin- 
burgh clinician,  Dr.  McKendrick,  physiologist,  and  Dr.  Alexander 
Bennett.  Their  researches  included  the  supposed  antagonism  of 
strychnia  and  chloral ;  atropia  and  Calabar  bean ;  chloral  and  Cala- 
bar bean ;  muriate  and  meconate  of  morphia  and  Calabar  bean ; 
sulphate  of  atropia  and  meconate  of  morphia ;  theine,  caffeine,  and 
guaranine  and  meconate  of  morphia  ;  Calabar  bean  and  strychnia ; 
and  bromal  hydrate  and  atropia.  The  next  year,  Dr.  Milner 
Fotbergill  $  made  a  report  to  the  British  Medical  Association  on 
the  antagonism  of  aconite  and  digitalis.  Soon  after  the  introduc- 
tion of  pilocarpus  (jaborandi)  and  the  isolation  of  its  alkaloid — 
pilocarpin — the  antagonism  of  this  agent  with  atropia  was  shown 
by  Yulpian.  §  An  extensive  research  into  the  general  subject  of 
physiological  antagonisms,  and  including  special  investigations  into 
the  antagonisms  of  chloral,  was  lately  undertaken  by  Professor 
Husemann,  the  results  being  published  in  1877.  Besides  these, 
several  memoirs  of  a  polemical  character  have  appeared  within  a 
few  years  past.  Of  these  I  may  mention  the  papers  of  KnapsteinJ 
Heubach,TT  and  Kay,**  in  addition  to  those  already  referred  to.  To 
such  importance,  indeed,  has  this  subject  attained,  that  no  research 
into  the  physiological  action  of  a  remedy  is  complete  until  its 
range  of  antagonisms  has  been  determined. 

From  this  brief  history  of  the  rise  and  development  of  the 
subject,  we  may  now  turn  to  the  examination  of  the  facts  which 
support  the  doctrine  of  the  antagonistic  action  of  remedies.  As 

*  "  Das  Chloral  Hydrat,  ein  neues  Hypnoticum  und  Anaestheticum,"  etc.,  Berlin, 
1869. 

f  "Brit.  Med.  Jour.,"  Jan.  25,  1875.     [Report  of  the  Committee.] 

\  Ibid.,  1876. 

§  "Gaz.  Hebdom.,"  6,  1875,  p.  81. 

||  Knapstein,  Adam,  "Berlin,  klin.  Woch.,"  47,  1878,  p.  691. 

TJ"  "Arch.  f.  experiment.  Pathol.  u.  Phannacol.,"  Band  viii,  p.  31. 

**  C.  Chr.  Kay,  "  Ueber  den  Antagonismus  zwischen  Opium  und  Belladonna."     Inaug. 
Diss.,  Jena,  1866. 


20  PHYSIOLOGICAL   ANTAGONISM. 

we  have  seen,  the  therapeutical  conception  which  has  obtained  the 
widest  and  most  enduring  influence  is  that  of  the  doctrine  of  con- 
traries. The  clinical  experience,  which  under  the  crude  and  im- 
perfect methods  and  the  slender  knowledge  of  past  times  led  to 
such  conclusion,  must  have  been  occupied  with  decisive  examples 
of  the  applicability  of  such  a  principle.  We  certainly  encounter 
many  such  examples  in  the  medical  practice  of  to-day.  We  might 
indeed  be  content  with  the  confirmatory  evidence  which  is  afforded 
by  carefully  conducted  clinical  observations.  There  is,  however, 
independent  testimony  of  another  kind.  The  doctrine  of  physio- 
logical antagonism — of  an  opposition  of  actions — finds  its  strongest 
support  in  the  mechanism  of  many  functions.  Let  me  ask  your 
undivided  attention  to  these  important  facts.  In  the  brain  are 
centers  for  the  inhibition  of  reflex  movements.  The  maximum 
amount  of  stimulation  both  increases  and  generalizes  reflex  action, 
if  communicated  to  the  same  part  of  the  spinal  cord ;  but,  if  a 
sensory  nerve  at  some  distant  point  is  irritated  at  the  same  time, 
the  reflex  action  which  would  have  been  produced  by  the  first 
stimulation  is  completely  and  entirely  restrained  or  inhibited. 
Here  an  opposition  of  actions  suspends  activity,  or,  to  express  the 
fact  in  technical  language,  reflex  actions  are  inhibited  or  suspended 
when  coincident  impressions  from  different  sources  are  made  on  the 
nerve  centers.  An  illustration  of  this  fact  is  afforded  in  the  arrest 
of  singultus  by  a  faradaic  current  applied  to  the  integument  of  the 
chest  or  abdomen.  If,  at  the  moment  the  spasm  of  the  diaphragm 
is  to  take  place,  a  strong  faradaio  current  be  passed,  no  attack 
occurs.  This  arrest  of  the  impending  spasm  is  due  to  the  simulta- 
neous impressions  made  on  the  spinal  center  concerned — one  from 
the  strongly  irritated  nerves  of  the  skin ;  the  other  from  the  dia- 
phragm, the  seat  of  spasm. 

In  the  medulla  oblongata  is  situated  a  center  of  extreme  re- 
flex sensibility — the  spasm  center  of  Nothnagel,  and  above  it  is 
an  inhibitory  center  of  reflex  movements — Setschenow's  inhibitory 
center.  If  there  were  not  some  antagonist  to  the  spasm  center, 
every  trifling  peripheral  irritation  would  produce  most  extravagant 
reflex  effects.  An  intimation  of  the  wild  irregularities  which 
would  ensue,  if  there  were  no  inhibiting  control  of  reflexes,  is 
afforded  in  the  abnormal  readiness  to  react  to  impressions  when 
the  influence  of  the  cerebrum  is  withdrawn  from  the  medulla 
oblongata  and  spinal  cord,  these  organs  acting  independently.  In 
the  cardiac  and  respiratory  mechanism  we  have  admirable  illustra- 


PHYSICAL   BASIS    OF   THE   PRINCIPLE.  21 

tions  of  opposing  forces  producing  order  and  rhythm.  The  move- 
ments of  the  vessels  are  regulated  by  a  vaso-motor  center  in  the 
medulla.  The  vascular  tonus  is  affected  by  the  condition  of  this 
center  and  its  associated  nerves.  By  the  opposed  action  of  the 
dilator  and  constrictor  forces,  the  vascular  tonus  is  maintained  at 
the  normal.  A  similar  mechanism  controls  the  cardiac  movements  ; 
there  is  a  motor  apparatus  for  carrying  on  the  action  of  the  heart, 
and  a  regulator  apparatus  for  restraining  the  movements  within 
proper  limits.  The  manner  in  which  the  action  of  the  heart  may 
be  affected  by  opposing  forces  is  admirably  shown  in  the  simple 
experiment  with  cold  and  heat.  Lay  a  turtle's  or  frog's  heart  on  a 
metallic  plate — it  will  continue  to  act  rhythmically  for  some  hours. 
Cooling  the  plate  with  ice  slows  the  heart,  and  will  presently  arrest 
its  movements ;  then,  on  applying  the  heat  of  the  spirit  lamp,  it 
begins  to  pulsate  again,  and  presently,  under  increased  warmth, 
acts  more  and  more  rapidly.  Expose  the  heart  of  a  frog  in  the 
usual  way,  remove  it  entire,  then  drop  upon  it  a  minute  quantity 
of  serum  containing  a  trace  of  muscarine — the  heart  will  be  ar- 
rested in  diastole.  On  adding  to  the  heart  a  few  drops  of  serum 
containing  0'2  per  cent,  of  atropia,  the  pulsations  begin  again 
and  go  on  energetically. 

The  reciprocity  of  action  provided  for  in  the  nervous  apparatus 
of  the  heart  and  blood-vessels  serves  to  restrain  variations  in  the 
blood  pressure,  and  to  keep  them  within  safe  limits.  If  the  arteri- 
oles  of  the  body  suddenly  dilate,  the  blood  pressure  as  quickly  falls, 
but  danger  to  the  circulation  is  prevented  by  an  increased  action  of 
the  heart.  Conversely,  when  the  blood  pressure  is  high,  the  incon- 
venience which  would  result  is  compensated  for  by  the  slowing  of 
the  heart.  Here  opposing  forces  maintain  an  equilibrium,  or  the 
normal.  Similar  regulating  mechanism  coordinates  the  respira- 
tory, cardiac,  and  vaso-motor  movements.  Yariations  in  the  blood 
pressure  and  in  the  pulse  occur  with  respiration,  the  pulse  quicken- 
ing during  inspiration,  and  slowing  during  expiration.  In  the 
movements  of  inspiration  and  expiration  ;  in  the  tidal  flow  of  secre- 
tion and  excretion ;  in  the  tonic  contraction  of  the  sphincters ;  in 
the  action  of  antagonistic  muscles,  etc.,  we  have -exhibited  the  be- 
neficent purpose  in  opposition  of  action. 

The  same  principle  obtains  in  physics.  The  undulations  by 
which  light  and  sound  become  cognizable  by  our  senses  are,  prob- 
ably, similar  to  those  by  which  impressions  and  impulses  are  trans- 
mitted along  nerves.  I  need  not  inform  this  audience  that  when 


22  PHYSIOLOGICAL   ANTAGONISM. 

rays  of  light  interfere  there  is  darkness,  and  that  when  rays  of 
sound  interfere  there  is  silence.  Interference  means  meeting  in 
.opposition  of  phase :  when  the  crest  of  one  wave  coincides  with 
the  depression  of  another,  the  surface  becomes  even.  When  two 
bodies  of  equal  weight  and  momentum  come  together  from  oppo- 
site directions,  both  are  arrested  at  the  point  of  impact.  The  phys- 
ical force,  electricity,  exists  in  a  neutral  or  unexcited  state,  when 
the  equilibrium  of  positive  or  negative  remains  undisturbed.  When 
the  equilibrium  has  been  ruptured,  and  the  two  modes  of  electrical 
force  are  separated,  they  combine,  when  afforded  the  opportunity  to 
do  so,  and  restore  the  equilibrium.  In  chemistry,  also,  do  we  find 
that  opposition  of  action,  combination  of  opposing  forces,  and  the 
formation  of  new  substances  are  constantly  going  on.  But  why 
multiply  examples  ?  Nothing  can  be  more  evident  than  that  the 
principle  of  antagonism  prevails  widely.  In  the  facts  supporting 
this  doctrine  which  I  have  brought  before  you,  there  would  seem  to 
be  a  justification  for  the  doctrine  of  antagonisms.  We  can  now 
proceed  with  confidence  to  the  study  of  individual  examples.  Aa 
the  question  was  first  concerned  with  opium  and  belladonna,  it  is 
most  fitting  to  commence  with  the  consideration  of  their  supposed 
antagonism. 

OPIUM  AND  BELLADONNA. 

In  the  observations  to  follow,  morphia  and  opium,  atropia  and 
belladonna,  will  be  used  synonymously. 

The  investigation  of  the  opposing  actions  ot  medicines  resolves 
itself  into  two  inquiries :  Does  the  antagonism  exist  ?  What  is  ita 
nature  ?  The  facts  which  have  been  accumulated  supporting  the 
doctrine  of  an  antagonism  between  opium  and  belladonna  are  clin- 
ical. The  experimental  facts  are  negative,  or  are  not  conclusive 
for  or  against  the  antagonism.  The  paper  of  Dr.  Norris  was  the 
first  attempt  to  collect  and  tabulate  the  results  of  clinical  experi- 
ence to  that  date.  I  have  collected  all  the  recorded  cases  which 
have  occurred  since,  and  have  added  some  unpublished  cases,  and 
two  which  were  unknown  to  Dr.  Norris,  or  escaped  his  search. 
The  table  of  Dr.  Norris  began  with  the  cases  of  Dr.  Thomas  An- 
derson, which  occurred  in  1854.  During  the  same  year  (1854)  Dr. 
W.  Lauder  Lindsay  *  reported  two  cases  of  opium  poisoning,  treated 
successfully  by  belladonna,  and  in  1857  Dr.  Sibson  f  published  a 

*  *  Assoc.  Med.  Journal,"  1864.  f  Ibid.,  Oct.  24,  1857. 


OPIUM    AND    BELLADONNA.  23 

case  in  which  opium  and  belladonna  were  taken  together,  the  effects 
of  the  one  being  neutralized  by  the  antagonistic  action  of  the  other. 
The  total  number  of  cases  of  opium  and  belladonna  poisoning, 
treated  with  the  antagonist,  is  120,  of  which  15  proved  fatal,  being 
12*5  per  cent,  of  failures.  These  statistics,  considered  apart  from 
any  other  question,  certainly  indicate  that  the  remedy  exerted  a 
favorable  influence  of  a  curative  kind — something  more  than  a  post 
hoc.  As,  in  almost  all  cases,  doses  of  the  poison  unquestionably 
lethal  were  administered,  the  agents  used  must  have  averted  death. 
In  very  few  cases  was  the  antagonist  only  administered.  The  part 
played  by  emetics,  the  stomach-pump,  coffee,  ambulation,  faradism, 
etc.,  when  these  were  used  as  well  as  atropia  or  morphia,  must  be 
estimated.  The  history  of  fatal  cases  is  peculiarly  instructive.  It 
is  necessary  to  know  why  the  antagonist  failed  to  exert  its  power. 
If,  in  a  case  in  all  respects  appropriate,  the  antagonist,  without  an 
adequate  explanation,  proved  useless,  the  antagonism  does  not  exist. 
The  success  of  a  remedy  used  with  a  njumber  of  other  remedies  may 
be  apparent  and  not  real.  It  is,  therefore,  highly  important  to  study 
the  cases  which  proved  fatal.  Not  to  weary  your  forbearance  too 
greatly,  I  condense  the  histories  into  the  smallest  possible  space. 

Unsuccessful  Cases. 

CASE  I  (Reported  by  Dr.  LudwigPollak.  "  Wiener  med.  Presse,"  xi,  28, 1870). 
— A  physician,  aged  sixty,  who  had  experienced  four  years  before  an  apoplectic 
seizure,  but  of  robust  constitution,  took,  with  suicidal  intent,  0'36  gramme  (about 
five  grains)  of  atropia.  At  the  end  of  six  hours  he  was  in  a  condition  of  profound 
insensibility,  with  labored  respiration,  expiration  blowing;  the  conjunctive 
injected,  corneas  glazed,  pupils  dilated  to  their  utmost;  and  urine  and  fasces 
passed  involuntarily.  A  syringeful  of  morphia  solution,  strength  not  stated,  was 
then  injected.  As  this  had  no  influence  on  the  pulse,  respiration,  or  pupils, 
another  injection,  half  the  first  amount,  was  given.  Death  occurred  in  fifteen 
hours  after  the  poison  was  taken. 

Commentary :  The  condition  of  the  brain,  the  large  dose  of  the 
poison  taken,  the  length  of  time  which  elapsed  before  the  antago- 
nist was  administered,  but  especially  the  inefficient  method  fol- 
lowed, serve  to  explain  the  untoward  result.  If  we  assume  that  the 
morphia  solution  had  the  usual  strength,  and  that  the  syringe  was 
of  the  usual  size,  the  amount  administered  could  not  have  exceeded 
two  grains.  The  proper  mode  of  introducing  the  morphia  in  such 
a  case  was  to  inject  one  fourth  to  one  half  a  grain  every  twenty  min- 
utes, until  some  movement  in  the  pupil,  or  change  in  the  respira- 


24  PHYSIOLOGICAL    ANTAGONISM. 

tion,  indicated  that  the  antagonistic  action  was  being  exerted.  Then 
the  result  of  the  antagonism  could  have  been  awaited  for  a  time. 
Having  had  a  cerebral  haemorrhage,  it  is  probable  that  additional 
mischief  was  done  by  atropia. 

CASE  II  (Reported  by  Mr.  James  Seaton.  "Med.  Times  and  Gaz.,"  Dec.  3, 
1859). — This  was  one  of  ten  cases  of  poisoning  by  belladonna  berries.  Opium  was 
nsed  in  all  of  the  cases  requiring  treatment,  with  success,  except  the  fatal  case. 
S.  W.,  aged  fourteen,  ate  an  unknown  quantity  of  the  berries,  which  produced 
dryness  of  the  mouth,  dilatation  of  the  pupil,  and  delirium.  At  the  expiration 
of  twelve  hours  the  child  vomited,  and  was  then  ordered  eight  minims  of  the 
tincture  of  opium  every  two  hours.  After  taking  16  minims,  the  dose  was  in- 
creased to  12  minims  every  hour  until  she  had  taken  60  minims.  The  opium 
was  then  suspended,  and  the  whole  amount  taken  was  given  after  the  first  twelve 
hours,  and  before  the  expiration  of  twenty-four  hours.  During  this  period,  the 
delirium  was  diversified  by  attacks  of  unconsciousness.  At  the  end  of  twenty- 
four  hours,  she  passed  into  a  condition  of  insensibility,  and  died  at  the  expiration 
of  twenty-nine  hours  from  the  time  of  eating  the  berries. 

Commentary :  The  whole  amount  of  tincture  of  opium  taken 
(72  minims)  was  about  equivalent  to  three  grains  of  crude  opium — 
an  amount  entirely  inadequate  to  counterbalance  a  lethal  dose  of 
belladonna.  Furthermore,  the  administration  of  the  antagonist  was 
suspended  when  most  demanded  by  the  violent  symptoms  of  bella- 
donna poisoning.  The  lesions  discovered  at  the  autopsy,  however, 
quite  explained  why  death  should  occur  despite  the  administration 
of  an  antidote.  The  heart  was  found  pale  and  flabby,  and  the 
pleural  surfaces  adherent  throughout. 

CASE  III  (Reported  by  Dr.  Samuel  W.  Gross.  "  Am.  Jour,  of  the  Med.  Sci.," 
Oct.,  1869,  p.  401).— Mrs.  H.,  a  stout  woman,  aged  forty-three,  took  at  8.20  A.  M. 
four  pills  containing  three  grains  of  atropia,  by  mistake  of  the  druggist.  In  a 
half  hour  she  had  lost  control  of  her  limbs,  was  deeply  flushed  and  delirious,  the 
hallucinations  consisting,  in  her  thinking  she  was  shopping,  sewing,  nursing  a 
child,  etc.  This  pleasant  delirium  lasted  about  ten  minutes,  when  she  sighed, 
yawned,  and  then  fell  into  a  deep  sleep,  and  at  10  A.  M.  could  not  be  roused. 
An  enema  and  a  number  of  emetics  were  administered.  At  11.15  one  of  the 
several  physicians  reported  that  Mrs.  H.  was  unconscious — eyes  closed,  pupils 
dilated,  muscular  system  relaxed,  except  of  the  jaw,  which  was  in  a  state  of 
trismus,  so  that  it  was  very  difficult  to  get  anything  into  the  stomach  ;  respira- 
tion labored,  pulse  good.  Half  a  grain  of  acetate  of  morphia  was  then  given. 
At  11.40,  Dr.  Gross  states,  the  muscular  system  was  relaxed,  the  trismus  having 
passed  off ;  the  skin  was  cool  and  moist;  pulse  106;  respiration  26  and  heavy 
without  stertor;  the  countenance  somewhat  livid;  the  conjunctivas  injected; 
pupils  dilated  three  fourths  and  insensible  to  light;  the  eyes  fixed,  with  a  bril- 
liant stare  ;  the  roof  of  the  mouth,  the  tongue,  and  the  soft  palate  were  parched 
and  glazed  ;  deglutition  was  impossible,  and  the  attempts  to  introduce  remedies 


OPIUM    AND    BELLADONNA.  25 

bj  the  mouth  brought  on  suffocative  attacks.  Half  a  grain  of  sulphate  of  mor- 
phia was  then  given  subcutaneously.  The  effect  of  this  was  a  scarcely  percepti- 
ble contraction  of  the  pupil,  reduction  of  the  respiration  to  20,  slight  stertor,  no 
change  in  the  pulse.  The  stomach-pump  was  then  used,  the  faradaic  current 
was  applied,  and  artificial  respiration  was  carried  on.  After  the  stomach  was 
washed  out,  whisky  and  ammonia  were  injected.  At  12  M.,  a  third  injection  of 
a  half  grain  of  morphia  was  inserted  under  the  skin.  In  fifteen  minutes  the  res- 
piration was  at  14,  but  very  decidedly  stertorous  ;  the  pulse  102,  full,  but  rather 
weak.  On  account  of  the  stertor,  no  more  morphia  was  given,  and  the  treat- 
ment subsequently  consisted  of  flagellation,  artificial  respiration,  and  faradiza- 
tion. Whenever  artificial  respiration  was  suspended,  the  breathing  became 
labored,  and  threatened  to  cease  entirely.  At  6.30  p.  M.,  however,  the  breathing 
became  more  natural,  and  at  T.45  all  the  measures  were  suspended,  as  the  patient 
appeared  to  be  in  a  quiet  sleep,  respiration  18,  pulse  108,  weak,  but  of  pretty 
good  volume.  At  8.45  p.  M.  the  respiration  increased,  r&les  became  audible  in 
the  chest,  the  face  turned  livid,  and  respiration  was  about  to  cease,  when  the 
measures  before  used  were  resorted  to,  and  veratria  ointment  was  in  addition 
vigorously  rubbed  in  over  the  spine  and  chest.  At  9  p.  M.  the  pulse  was  at  128, 
respiration  28,  and  she  executed  various  voluntary  movements  when  hurt  by  the 
flagellation.  At  10  p.  M.  she  cried  out,  "  Oh,  my !  "  and  turned  on  her  side. 
At  11  P.  M.,  in  response  to  the  question,  she  replied  that  she  was  "  better."  Ar- 
tificial respiration  had  been  kept  up  at  intervals.  Some  urine  was  drawn  off, 
and  a  small  quantity  was  injected  into  the  family  cat,  producing  decided  dilata- 
tion of  the  pupil.  At  11.10  P.  M.  symptoms  of  suffocation  suddenly  set  in,  and, 
notwithstanding  the  vigorous  application  of  the  methods  before  used,  she  soon 
expired.  At  the  autopsy,  the  superficial  veins  of  the  body  were  found  gorged, 
and  there  were  extensive  suggillations  posteriorly.  The  veins  of  the  brain  were 
very  full,  there  was  much  serum  in  the  sub-arachnoid  space,  and  the  cerebral 
tissue  was  generally  softened  [by  imbibition,  probably].  The  lungs  were  deeply 
congested,  and  the  tissue  of  the  heart  was  soft  and  easily  torn. 

Commentary :  Although  I  have  placed  this  among  the  unsuc- 
cessful examples  of  atropia  poisoning  treated  by  morphia,  it  can 
only  be  so  regarded  with  some  distinct  limitations.  The  quantity 
of  morphia  required  to  antagonize  such  a  dose  of  atropia  is  hardly 
less  than  six  grains.  The  first  injection  was  given  in  three  hours 
after  the  atropia  was  taken,  the  last  one  in  four  hours,  and  nearly 
twelve  hours  before  death.  After  the  first  injection  the  pulse  was 
reduced  to  108,  thetrismus  had  ceased,  the  skin  was  cool  and  moist, 
and  the  respirations  were  20,  without  stertor.  These  were  very  fa- 
vorable indications,  and  were  produced  by  one  half  a  grain  of  mor- 
phia only.  Under  these  circumstances,  it  seems  to  me  it  would 
have  been  better  to  await  the  further  antagonistic  action  of  morphia, 
for,  although  the  amount  given  was  insufficient  to  antagonize  the 
quantity  of  atropia  taken,  it  will  be  shown  hereafter  that  the  con- 
dition of  the  respiration  and  circulation  was  such  as  to  justify  the 


26  PHYSIOLOGICAL   ANTAGONISM. 

belief  that  the  antagonism  was  sufficient.  Furthermore,  by  this 
time,  no  inconsiderable  part  of  the  atropia  had  been  eliminated,  as 
proved  by  the  effect  of  the  subcutaneous  injection  of  the  urine  in 
the  cat.  It  is  not  a  little  important,  as  I  shall  hereafter  demon- 
strate, to  note  the  rate  of  elimination  of  the  poison  as  a  factor,  be- 
fore deciding  on  the  quantity  of  the  antagonist  to  be  used.  Another 
element  in  this  case,  that  goes  far  to  impair  its  value  as  a  negative 
fact,  is  the  condition  of  the  heart.  The  patient  was  a  rather  obese 
subject,  and  hence  it  is  probable  the  heart  muscle  was  in  a  state  of 
more  or  less  advanced  fatty  degeneration.  The  fatal  result,  at  last, 
appears  to  have  been  caused  by  failure  of  the  heart. 

CASE  IV  (Reported  by  F.  A.  Southam,  M.  D.  "  Brit.  Med.  Jour.,"  June  8r 
1878,  p.  824). — A  man,  aged  thirty-eight,  had  taken  two  ounces  of  laudanum 
eighteen  hours  before  treatment  was  instituted.  He  was  then  in  a  state  of  pro- 
found coma,  the  pupils  were  contracted  to  the  size  of  pins'  points,  the  conjunc- 
tivas were  insensible,  the  respirations  were  four  a  minute,  the  pulse  was  very 
quick  and  irregular.  The  treatment  consisted  in  the  application  of  heat,  artificial 
respiration,  faradization,  and  the  hypodermic  injection  of  atropia.  The  patient 
received  in  all  five  injections,  of  ^  grain  each — the  first  at  7.30  p.  M.,  the  second 
at  7.45,  the  third  at  8.30,  the  fourth  at  9.30,  and  the  fifth  at  9.45  p.  M.,  the  man 
dying  at  10  p.  M.  The  immediate  effect  of  each  injection  was  to  raise  the  respi- 
ration to  near  normal,  and  to  improve  the  tone  of  the  pulse,  but  the  effect  was 
brief  and  lessened  with  each  injection.  Extensive  congestion  of  the  lungs  was 
found  after  death. 

Commentary:  This  case  is  complete  in  all  the  terms  of  the 
problem.  The  poison  was  entirely  absorbed,  and  there  were  no 
complications  or  accidents  to  affect  the  result.  An  obvious  defi- 
ciency existed  in  the  treatment,  however.  The  good  accomplished 
by  each  injection  was  most  conspicuous,  but  the  impression  made 
was  so  transient  that  no  effect  remained  over  to  the  next  dose.  As 
the  whole  of  the  poison  taken  probably  remained  in  the  blood,  the 
function  of  excretion  being  suspended  by  the  narcotism,  the  whole 
amount  of  atropia  administered  should  have  been  given  at  one  dose, 
and  repeated  according  to  necessity.  In  a  case  almost  exactly  sim- 
ilar, except  that  the  quantity  of  laudanum  taken  was  somewhat 
less,  Dr.  Milner  Fothergill  gave  at  once  one  grain  of  atropia  sul- 
phate, with  entire  success.  It  is  evident  that  the  quantity  of 
atropia  administered  was  not  sufficient  to  antagonize  the  opium, 
although  the  return  of  the  reflex  sensibility,  the  improvement  in  the 
respiration,  and  the  dilatation  of  the  pupil  indicated  that  a  counter- 
balancing action  was  exerted,  if  only  for  a  brief  period.  The  long 
duration  x)f  the  toxic  symptoms  before  the  administration  of  the 


OPIUM    AND    BELLADONNA.  27 

antagonist  was  not  without  influence,  for  the  carbonic-acid  narcosis 
and  the  congestion  of  the  lungs  were  developed  when  the  respira- 
tions were  only  four  a  minute.  Nevertheless,  an  efficient  adminis- 
tration of  the  antagonistic  would  have  secured  a  favorable  result. 

CASE  V  (Reported  by  Dr.  G.  E.  Paget.  "  Brit.  Med.  Jour.,"  Sept.  15,  1877, 
p.  3Y4). — A  child,  three  and  a  half  years  old,  received  an  unknown  quantity  of 
laudanum,  but  only  sufficient  to  cause,  in  two  and  a  half  hours,  a  drowsy  loot. 
The  pupils  were  very  small.  The  drowsiness  increasing,  notwithstanding  vom- 
iting, strong  coffee,  and  ambulation,  -j-i-g-  grain  of  sulphate  of  atropia  was  injected 
in  four  hours  after  the  poison  had  been  taken.  No  effect  being  produced  by 
this,  another  injection  of  ^-5-  of  a  grain  of  atropia  was  inserted.  After  this  the 
pupil  slowly  dilated,  and,  in  an  hour  and  a  half,  had  attained  extraordinary  size, 
but  notwithstanding  this  the  stupor  deepened  into  coma.  In  five  and  a  half 
hours,  the  appearance  of  the  child  was  almost  death-like.  Artificial  respiration 
was  diligently  applied  for  many  hours ;  and  at  the  expiration  of  twenty -four 
hours,  decided  improvement  was  manifest,  but  unfortunately  proved  temporary. 
Four  hours  after  the  pupils  became  affected  by  the  atropia,  they  had  regained 
their  natural  size.  Death  ensued  in  twenty-eight  hours  after  the  poison  was. 
taken. 

Commentary :  The  important  fact  in  this  case  is,  the  predomi- 
nant effect  of  atropia  on  the  pupil,  and  the  apparently  slight  effect 
on  the  pulse,  respiration,  and  cerebrum.  The  quantity  of  laudanum 
swallowed  being  unknown,  no  guide,  except  the  state  of  the  func- 
tions, existed  for  the  administration  of  atropia.  It  is  probable 
indeed  that  the  first  injection  of  atropia  was  sufficient,  as  after  the 
expiration  of  four  hours,  the  child  was  merely  "drowsy."  The 
lividity,  death-like  pallor,  and  coldness  of  the  extremities  came  on 
after  the  second  injection.  The  report  further  states  that,  "while 
he  was  in  the  heavy  stupor,  his  arms  were  several  times  extended 
in  tonic  spasms,  and  his  eyes  now  and  then  squinted  divergently."" 
At  this  time  "  his  pupils  were  so  dilated  that  scarcely  a  part  of  the 
iris  could  be  seen."  As  atropia  produces  more  or  less  tetanizing 
action,  it  is  probable  that  the  tonic  spasms  were  produced  by  it. 
From  this  point  of  view,  the  action  of  the  opium  being  slight,  it 
would  have  been  better  to  await  the  influence  of  the  first  injection. 
Death  occurring,  probably  from  exhaustion,  in  twenty-eight  hours, 
would  seein  to  be  a  not  unnatural  result  of  the  poison,  the  artificial 
respiration,  the  emetic,  the  ambulation,  the  flagellation,  the  atro- 
pia, etc.,  acting  on  the  system  of  a  child  three  and  a  half  years  old. 

CASES  VI  and  VII  (Reported  by  Dr.  F.  L.  Haynes.  "Phila.  Med.  Times," 
Sept.  14,  1878). — Two  cases  of  opium  poisoning — the  first  by  a  half-ounce  of 
laudanum ;  the  second  by  an  ounce  of  crude  opium.  In  the  first  case,  there 


28  PHYSIOLOGICAL    ANTAGONISM. 

were  two  injections  of  atropia— one  of  TV,  the  other  of  ^  grain,  without  effect 
on  the  respiratory  function.  The  amount  of  the  antagonist  was  much  too  small. 
In  the  second  case,  there  were  four  or  five  doses  of  ^V  of  a  grain  of  atropia, 
equivalent  to  one  fourth  of  a  grain  in  the  aggregate,  to  antagonize  an  ounce  of 
crude  opium.  It  is  merely  necessary  to  state  the  facts  to  demonstrate  the  source 
of  failure,  if  there  were  no  other  unfavorable  conditions  present. 

CASE  VIII  (Reported  by  Dr.  James  Johnston.  "  Med.  Times  and  Gaz.,"  Sept. 
V,  1872). — A  man,  aged  thirty-two,  took  three  drachms  of  the  extract  of  opium 
at  8  p.  M.  At  11  P.  M.  he  was  profoundly  comatose ;  pulse  121,  weak  and  irregu- 
lar; reflexes  abolished.  At  1  A.  M.  a  quarter  of  a  grain  of  atropia  was  injected. 
At  3.30  A.  M.  the  face  was  slightly  flushed  and  the  pupils  were  dilated ;  pulse 
130,  weak  and  intermittent.  At  9  A.  M.  another  injection  of  the  same  quantity 
was  inserted.  Respiration  was  then  softer,  pulse  still  very  weak,  but  he  could 
be  roused  slightly,  and  he  swallowed  a  little  ammonia  and  coffee ;  but  he  gradu- 
ally failed,  and  died  at  5  p.  M. 

CASE  IX  (same  source.  Loco  citat.). — A  girl  of  sixteen  received  ten  drachms 
of  extract  of  opium.  Six  hours  afterward  the  stomach-pump  was  used,  and  a 
half  grain  of  atropia  was  injected.  In  an  hour  the  pulse  was  almost  impercepti- 
ble, and  death  ensued  in  two  hours  after  the  atropine  was  inserted. 

CASE  X  (same  source.  Loco  citat.}. — A  man,  aged  thirty-eight,  took  three 
drachms  of  the  extract  of  opium  at  10  A.  M.  At  3  p.  M.  he  was  comatose,  with 
stertorous  breathing,  and  the  pulse  was  weak  and  irregular.  One  fourth  of  a 
grain  of  atropia  was  given,  after  the  stomach  had  been  thoroughly  emptied  by 
the  pump.  At  4.30  p.  M.  the  pupils  suddenly  dilated  to  a  great  extent,  the  respi- 
ration became  hurried  and  irregular,  and  the  pulse  ceased  at  the  wrist,  death 
occurring  at  5.30  p.  M. 

CASE  XI  (same  source.  Loco  citat.}. — A  woman,  aged  seventeen,  took  an 
unknown  quantity  of  opium,  and  was  found  in  a  state  of  profound  coma,  pulse 
150,  respiration  slow  and  stertorous.  Half  a  grain  of  sulphate  of  atropia  was 
then  injected,  and  artificial  respiration  was  carried  on,  but  without  effect. 

CASE  XII  (same  source.  Loco  citat.}. — A  woman,  aged  thirty -six,  took  two 
drachms  of  extract  of  opium  at  8  A.  M.  At  1.20  p.  M.  she  was  drowsy,  but 
could  be  roused  up  to  walk  about,  and  was  vomited  by  sulphate  of  zinc.  At  2.20 
p.  M.,  severe  coma  setting  in,  the  cold  douche  was  used,  and  at  3  a  half  grain  of 
sulphate  of  atropia  was  injected.  At  4,  the  face  was  slightly  flushed,  and  the 
pupils  were  dilated  a  little,  but,  at  5,  convulsions  of  the  extremities  and  face  be- 
gan, and  she  died  at  5.30  p.  M. 

CASE  XIII  (same  source.  Loco  citat.}. — A  woman,  aged  twenty-seven,  took 
a  half  ounce  of  extract  of  opium  at  9.30  A.  M.  At  noon  the  stomach-pump  was 
used,  and  a  half  grain  of  sulphate  of  atropia  was  injected.  She  was  then  in  a 
profound  coma,  with  stertorous  breathing,  her  pulse  was  small  and  quick,  her  lips 
livid.  At  3  P.  M.  convulsions  set  in,  and  death  ensued  in  a  few  minutes. 

Commentary ;  The  six  fatal  cases,  from  the  eighth  to  the  thir- 
teenth, inclusive,  were  reported  by  Dr.  James  Johnston,  of  the 
Chinese  Hospital,  at  Shanghai,  who  has  had  unequaled  opportunities 
of  clinical  experience  in  opium  poisoning.  He  thus  comments  on 
the  fatal  cases :  "  Of  the  fatal  cases  in  which  atropine  was  used,  the 


OPIUM    AND    BELLADOlSTffA.  29 

first  one  reported  lived  for  eighteen  hours,  and  the  action  of  the 
atropine  was  very  manifest,  as  the  patient  partially  recovered  con- 
sciousness, and  did  not  perish  from  the  comatose  effect  of  opium, 
but  from  exhaustion  following  that  condition.  In  the  second  fatal 
case,  the  patient  was  only  two  hours  and  a  half  under  treatment, 
and  died  from  cerebral  apoplexy.  The  third  was  under  treatment  a 
little  over  two  hours,  and  died  from  cerebral  effusion.  The  fourth 
was  two  hours  under  treatment,  and  died  from  exhaustion.  The 
fifth  was  under  treatment  for  five  hours,  and  died  in  convulsions. 
The  sixth  also  died  in  convulsions,  and  was  under  treatment  for 
three  hours  and  a  half."  To  these  criticisms  we  may  add  that  there 
was  no  proper  adjustment  of  the  dose  of  the  antagonist  to  the  effect 
of  the  poison,  and  that  in  two  of  the  cases  the  atropia  was  without 
effect,  owing  to  the  depth  of  the  narcotism  and  the  suspension  of 
absorption.  As  the  experience  of  Dr.  Johnston  is  quite  unpre- 
cedented in  respect  to  opium  poisoning,  I  quote  his  opinion  of  the 
value  of  atropia  as  an  antidote :  "  The  class  of  cases  in  which  the 
wonderful  powers  of  atropine  as  an  antidote  to  opium  poisoning  are 
most  marked  is  where  profound  coma  exists;  and,  for  such  a  con- 
dition, I  know  of  no  other  remedy.  You  may  try  to  drag  the 
patient  about,  use  the  cold  douche,  carry  on  artificial  respiration 
assiduously,  give  stimulants  of  every  description  ;  all  in  vain — the 
patient  remains  comatose  and  lifeless.  Administer  atropine,  and 
the  effects  are  marvelous :  the  pupils  dilate ;  the  face  becomes 
flushed  ;  the  respiration  loses  its  stertorous  character,  and  becomes 
slow  and  tranquil;  the  pnlse  is  diminished  in  frequency,  and  be- 
comes stronger ;  the  patient  slumbers  peacefully  for  several  hours, 
and  at  last  wakes  up  conscious." 

CASE  XIV  (Reported  by  Dr.  H.  0.  Wood.  "  Phila.  Med.  Times,"  Aug.  9, 1873.) 
— A  man,  aged  sixty-three,  received  for  an  attack  of  cholera  morbus  1£  grain  of 
morphia  and  1J  grain  of  opium.  For  the  opium  narcosis  which  ensued,  there 
were  administered  fourteen  injections  of  atropia,  aggregating  -J-  grain.  The  last 
injection  was  administered  twenty-four  hours  before  death,  which  ensued  in 
twenty-eight  hours  after  the  ingestion  of  the  poison. 

Commentary :  The  probable  existence  of  an  underlying  morbid 
state  and  the  exhaustion  caused  by  the  cholera  morbns  must  be 
taken  into  account  in  estimating  the  precise  share  of  atropia  in  the 
result.  Such  a  case  is,  indeed,  of  small  value  for  determining  the 
existence  of  an  antagonism  between,  or  the  opposed  action  of,  atro- 
pia and  morphia,  owing  to  the  uncertainty  which  must  attend  the 
relative  influence  of  the  several  factors  concerned. 


30  PHYSIOLOGICAL   ANTAGONISM. 

CASE  XV  (Reported  by  Dr.  Beddoe.  "Lancet,"  July  16,  1870).— A  woman, 
aged  sixty-eight,  swallowed  a  teaspoonful  of  belladonna  liniment  at  11  A.  M. 
Emetics  and  the  stomach-pnmp  were  used  without  effect.  At  2.45  p.  M.  she  re- 
ceived twenty  minims  of  laudanum,  and  soon  after  an  injection  of  one  third  of  a 
grain  of  morphia  acetate.  Previous  to  this,  she  could  still  swallow  fluids,  and, 
although  delirious,  could  understand  what  was  said  to  her.  At  3.30  p.  M.  the 
morphia  injection  was  repeated,  one  fourth  of  a  grain  being  given.  She  was  then 
reported  to  be  less  active  in  her  movements,  and  seemed  more  drowsy.  After 
the  last  injection  she  became  comatose,  and  breathed  stertorously  if  undisturbed 
for  a  few  moments.  Her  pulse  was  then  100,  and  of  good  strength,  and  the 
pupils  were  widely  dilated.  At  4.30,  a  third  injection  of  morphia — one  third  of 
a  grain — was  given.  At  6.15  P.  M.  she  was  decidedly  comatose,  and  ceased  to 
breathe  unless  artificial  respirations  were  kept  up.  At  3  A.  M.,  sixteen  hours 
after  taking  the  poison,  she  died.  The  autopsy  disclosed  venous  hyperaemia  of 
the  brain  and  lungs. 

Commentary :  The  strength  of  the  belladonna  liniment  of  the 
British  Pharmacopoeia  is  four  times  that  of  the  extract  of  the  leaves. 
The  patient  being  able  to  swallow  without  difficulty  three  hours 
after  the  ingestion  of  the  poison,  and,  although  delirious,  returning 
correct  replies  to  the  interrogatories  addressed  her,  indicate  that 
the  toxic  effect  was  not  great.  Under  these  circumstances,  small 
doses,  only,  of  the  antagonist  were  proper.  When  decided  stupor 
followed  the  second  injection,  the  third  should  have  been  withheld, 
notwithstanding  the  persistent  dilatation  of  the  pupil,  for,  as  I  shall 
show,  this  sign  is  not  without  qualification.  In  fact,  we  find  that 
the  reporter  of  the  case  remarks,  "  excepting  the  dilatation  of  the 
pupil,  the  patient's  condition  exactly  resembled  that  of  opium  poi- 
soning, after  the  delirium  had  subsided  into  coma." 


LECTUEE  II. 

OPIUM    AND   BELLADONNA,    CONTINUED. 

A  EEVIEW  of  the  fatal  cases  of  opium  or  belladonna  poisoning, 
in  which  the  antagonist  was  the  principal  means  of  treatment,  less- 
ens their  importance  as  negative  testimony.  The  maximum  and 
minimum  toxic  doses  proving  fatal  are  equaled  by  the  doses  re- 
covered from.  Hence  it  may  be  assumed  that,  if  the  results  are  not 
fortunate  in  any  case,  we  have  a  right  to  conclude  that  one  of  three 
propositions  is  true :  that  the  toxic  dose  was  excessive ;  that  it  had 
been  acting  so  long  that  the  tissues  could  no  more  react  to  the  an- 
tagonist ;  or,  that  the  antagonism  was  defeated  by  the  failure  of 
some  vital  organ.  In  the  fifteen  fatal  cases,  there  were  eleven  in- 
efficiently treated ;  in  six  of  these  but  a  single  injection  was  prac- 
ticed, and  in  all  the  actual  amount  required  to  antagonize  the  toxic 
agent  was  not  given.  In  two  of  the  fifteen  cases  the  antagonist  was 
used  in  excess,  and  the  fatal  result  in  both  may  fairly  be  attributa- 
ble to  this  preponderating  action.  In  six,  the  persons  poisoned  were 
already  in  a  pathological  state :  one  had  experienced  an  apoplectic 
stroke ;  one  died  from  cerebral  haemorrhage,  and  another  from  cere- 
bral effusion  ;  one  was  suffering  from  the  effects  of  a  cholera  morbus ; 
one  had  a  fatty  heart ;  and  one  had  general  adhesions  of  both  pleu- 
ral  surfaces.  If,  indeed,  all  the  sources  of  fallacy  were  excluded, 
the  fatal  cases  would  scarcely  aspire  to  the  dignit}r  of  negative  facts. 
So  preponderating  are  the  examples  of  success,  and  of  so  little  value 
the  negative  cases,  that  a  high  degree  of  certainty  must  be  admitted 
to  inhere  in  the  application  of  the  antagonism  of  opium  and  bel- 
ladonna. 

With  respect  to  the  successful  cases,  if  it  be  claimed  that  one 
agent  may  prevent  death  from  the  other,  it  must  be  shown  that  the 
quantity  of  poison  taken  was  really  lethal.  As  readily  determined 


32  PHYSIOLOGICAL    ANTAGONISM. 

as  this  may  appear  to  be,  it  is  nevertheless  difficult,  even  impossible, 
in  respect  to  any  single  instance.  We  find  in  Taylor  "  On  Poisons 5> 
that  four  grains  of  crude  opium,  two  drachms  of  laudanum,  and  one 
grain  of  muriate  of  morphia  have  each  proved  fatal  to  adults.  On 
the  other  hand,  as  much  as  eight  ounces  of  laudanum  have  been 
taken  without  injury.  In  one  instance  a  drachm  of  the  extract  ot 
belladonna  did  not,  and,  in  another,  two  grains  of  atropia  did,  cause 
death.  •  The  remarkable  variations  in  the  toxic  effects  of  poisons, 
due  to  idiosyncrasy,  to  the  state  of  the  stomach,  to  the  fullness  of  the 
vascular  system,  to  habit,  etc.,  must  be  taken  into  account  in  esti- 
mating the  influence  of  the  antagonist  in  the  curative  result.  liar- 
ley  has  collected  a  number  of  cases,  in  which  an  unquestionably  lethal 
quantity  of  the  poison  failed  to  cause  death,  when  not  interfered 
with  by  the  action  of  an  antagonist,  or  by  any  specific  treatment. 
It  is  necessary  therefore  to  ascertain,  definitely,  whether  in  each  one 
of  the  106  *  successful  cases  the  patient  had  received  a  dose  proba- 
bly lethal,  or  presented  symptoms  indicating  that  such  quantity  had 
been  taken.  On  the  other  hand,  the  antagonism  may  be  admitted 
to  exist,  if  decided  symptoms  occasioned  by  one  may  be  removed 
by  the  administration  of  the  other.  Under  the  latter,  may  be  clas- 
sified the  cases  of  Graefe  and  Fronmuller,  in  which  symptoms  of 
poisoning  were  produced  by  a  half  grain  of  sulphate  of  atropia. 
The  antagonizing  action  may  be  just  as  clearly  exhibited  in  such  as 
in  undoubtedly  lethal  cases.  Among  the  patients  receiving  the 
largest  amount  of  poison  and  recovering,  were  one  having  had  thirty 
grains  of  crude  opium  ;  one,  an  ounce  and  a  half  of  laudanum  ;  one,, 
twelve  to  fifteen  grains  of  morphia;  one,  five  grains  of  morphia  ; 
one,  six  grains  of  morphia ;  one,  a  teaspoonful  of  belladonna  lini- 
ment, which  is  of  four  times  the  strength  of  the  extract;  one,  two 
grains  of  morphia  and  one  grain  of  atropia  together,  etc.  In  all  but 
two,  the  quantity  of  poison  received  was  sufficient,  cceteris  paribusy 
to  cause  lethal  effects,  and  this  collection  of  cases,  therefore,  fulfills 
the  conditions  necessary  to  the  determination  of  the  question  of  an- 
tagonistic action  in  its  entirety. 

While  the  necessary  conditions  are  not  wanting  in  the  examples 
of  antagonistic  action  collected  here,  there  is  a  source  of  fallacy  in 
the  fact  that  various  approved  expedients  were  resorted  to,  in  ad- 
dition to  the  exhibition  of  the  antagonist.  An  emetic  or  the  stom- 
ach-pump, faradism,  ambulation,  various  kinds  of  irritation  of  the 

•Another  case  obtained  from  "  N.  Y.  Med.  Jour."  just  before  this  lecture. 


OPIUM    AND    BELLADOJSNA.  33 

surface  (chiefly  flagellation),  and  artificial  respiration  were  employed 
to  a  greater  or  less  extent.  Sometimes  good  effects  were  obtained 
by  these  measures,  but  the  antagonism  could  not  be  questioned 
when  the  respiration,  the  cardiac  movements,  and  the  state  of  the 
pupil  indicated  the  action  of  the  antagonist.  Yery  often  the  pro- 
tracted efforts  at  resuscitation,  in  the  way  of  flagellation,  ambula- 
tion,  artificial  respiration,  and  faradization,  exhaust  the  patient.  In 
several  of  the  cases  it  is  evident  that  these  ill-advised  measures  con- 
tributed to  a  fatal  result,  especially  the  protracted  ambnlation  and 
flagellation.  I  quote  on  this  point  the  fifth  and  last  conclusion 
of  Dr.  Johnston,  of  Shanghai,  China:  "When  the  system  is  fair- 
ly under  the  influence  of  atropine,  with  respiration  tranquil,  how- 
ever slow  it  may  be,  it  is  undesirable  to  interfere  by  artificial  res- 
piration, as  it  only  embarrasses  the  breathing  and  interferes  with 
the  tranquil  sleep  which  usually  follows  the  exhibition  of  atro- 
pine." 

All  sources  of  fallacy  eliminated,  the  antagonizing  action  of 
opium  and  belladonna  is  supported  by  a  great  array  of  cases.  The 
clinical  evidence  seems  conclusive.  We  have  now  to  examine  the 
evidence  in  opposition  based  on  experiments  on  animals.  This  is 
deserving  of  attentive  consideration.  Unfortunately,  the  first  ob- 
servations made  on  animals  by  Brown-Sequard,*  Bois,f  Camus,  J 
Onsum,  §  and  Harley,  ||  were  vitiated  by  their  neglect  to  ascertain 
the  exact  lethal  dose  of  opium  or  of  belladonna.  In  1866,  Erle- 
meyer  T  published  an  experimental  research,  in  which,  for  the  first 
time  on  animals,  the  nature  of  the  opposed  action  of  morphia  and 
atropia  was  ascertained.  He  demonstrated  that  these  agents  were 
opposed,  or  antagonistic,  in  respect  to  their  influence  over  the  pulse, 
respiration,  pupil,  and  brain,  and  that  they  were  much  better  borne 
when  given  in  combination  than  when  given  separately.  Conclu- 
sions in  some  respects  the  same  were  reached  by  Harley.  He  thus 
formulates  the  results  of  his  experiments  on  dogs  : 

"  1.  Belladonna,  when  administered  simultaneously  with  opium, 
more  or  less  completely  prevents  nausea  and  vomiting,  and,  when 
given  previously,  entirely  prevents  these  effects.  2.  Whether  given 
previously,  simultaneously,  or  subsequently,  atropia  completely 
counteracts  the  respiratory  restraint  on  the  free  action  of  the  heart, 
which  is  so  prominent  an  effect  of  the  operation  of  opium.  We  can 

*  "  Jour,  de  Physiol.,"  etc.,  loc.  cU.  f  "  Gaz.  des  Hop.,"  71,  1865. 

J  "  Gaz.  Hebdom.,"  2  ser.,  xii,  32,  1865.      §  "  Schmidt's  Jahrbiicher,"  vol.  cxxviii,  p.  288. 

|  "  The  Old  Vegetable  Neurotics,"  loc.  cit.   f  "  Berlin,  klin.  Woch.,"  2,  1866. 

3 


34  PHYSIOLOGICAL    ANTAGONISM. 

wish,"  he  further  says,  "  for  no  more  perfect  an  illustration  of  the 
beneficial  influence  of  a  medicine  under  suitable  conditions  than 
that  afforded  by  the  simple  and  direct  action  of  atropia  in  relieving 
the  impending  syncope  which  often  persists  for  many  hours  after  a 
dose  of  opium.  ...  3.  While  the  spinal  effects  of  opium  on  the 
muscles  of  organic  life  are  thus  counteracted  by  the  stimulant  action 
of  atropia  on  the  sympathetic,  the  cerebral  and  anaesthetic  effects 
are  intensified  and  prolonged  by  belladonna,  and  hypnosis  is  con- 
verted into  narcosis,"  etc. 

In  1870,  Dr.  Koning  *  published  a  dissertation  on  the  supposed 
antagonism  of  morphia  and  atropia,  his  research  being  conducted  on 
animals.  As  had  his  predecessors  in  this  inquiry,  Koning  decided 
adversely  to  the  existence  of  this  antagonism,  although  he  noted  the 
antagonizing  influence  of  these  agents  on  the  pupil,  the  respiration, 
and  the  action  of  the  heart.  In  1873,  Frohlich,f  of  Wurzburg,  ex- 
perimented with  these  agents  on  frogs  and  cats.  His  experiments 
rather  indicated  the  existence  of  points  of  opposition,  but  not  suffi- 
cient to  prevent  death  from  a  lethal  dose  of  both  agents.  In  1874  J 
appeared  the  report  of  the  committee  appointed  by  the  British 
Medical  Association,  Professor  J.  Hughes  Bennett,  M.  D.,  of  Edin- 
burgh, Chairman.  In  making  the  report  on  this  division  of  the  sub- 
ject— the  antagonism  of  morphia  and  atropia — the  reporter  says : 
"  Extraordinary  pains  were  taken  to  determine  the  question  whether 
or  not  morphia  and  atropia  were  antagonistic  of  one  another;  and 
the  researches  now  to  be  described  will  be  found  to  add  largely  to 
our  precise  and  exact  knowledge  as  compared  with  the  unfounded 
and  contradictory  opinions  which  have  hitherto  prevailed.  The 
conclusions  at  which  they  arrived,  after  experiments  on  the  rabbit, 
chiefly,  are  as  follows : 

"  1.  Sulphate  of  atropia  is  physiologically  antagonistic  to  the 
meconate  of  morphia  within  a  limited  area.  2.  Meconate  of  mor- 
phia does  not  act  beneficially  after  a  large  dose  of  sulphate  of  atro- 
pia, for  in  these  cases  the  tendency  to  death  is  greater  than  if  a  large 
dose  of  either  substance  had  been  given  alone.  3.  Meconate  of 
morphia  is  not  specifically  antagonistic  to  the  action  of  sulphate  of 
atropia  on  the  vaso-inhibitory  nerves  of  the  heart ;  and,  4,  the  bene- 
ficial effect  of  sulphate  of  atropia  after  the  administration  of  large 
doses  of  meconate  of  morphia  is  probably  due  to  the  action  sulphate 

*  "  Schmidt's  Jahrbiicher,"  rol.  cxlix,  p.  18. 

f  "  Pharmakologische  Untersuchungen,"  1873,  pp.  224  and  231. 

\  "  Brit.  Med.  Jour.,"  1874,  vol.  ii,  various  Nos. 


OPIUM   AND    BELLADONNA.  35 

of  atropia  exercises  on  the  blood-vessels.  ...  It  may  also  assist  up 
to  a  certain  point,  not  precisely  fixed  in  these  experiments,  by  stim- 
ulating the  action  of  the  heart  through  the  sympathetic,  and  obvi- 
ating the  tendency  to  death  from  deficient  respiration  observed  after 
large  doses  of  morphia." 

In  1876  the  same  line  of  research  was  taken  up  by  Corona,  on 
dogs  and  cats.  He  arrived  at  the  conclusion  that  a  partial  physio- 
logical antagonism  existed  between  morphia  and  atropia ;  but  not 
a  therapeutical  antagonism — for,  while  morphia  is  useful  in  atropia 
poisoning,  in  poisoning  by  morphia  the  effects  are  not  removed  by 
atropia.  In  this  opinion  Corona  stands  quite  alone.  In  the  follow- 
ing year,  1877,  Dr.  Hans  Heubach  reviewed  the  literature  of  the 
subject,  and  undertook  a  new  investigation  of  the  supposed  antag- 
onism, confining  his  experimental  research  to  animals.  These 
investigations,  carried  on  at  Binz's  laboratory,  at  Bonn,  support 
the  view  of  a  limited  antagonism  in  the  cardiac  and  respiratory 
organs. 

The  various  experiments  on  animals  have  been  singularly  uni- 
form in  results,  how  much  soever  the  interpretations  'put  on  the 
facts  may  differ.  In  the  first  place,  it  is  perfectly  evident  that, 
when  lethal  doses  of  the  two  poisons  are  administered,  fatal  results 
almost  invariably  ensue — not  invariably,  since  the  Bennett  com- 
mittee succeeded  in  a  very  few  out  of  a  great  many  trials.  If  the 
experiment  of  Bois,  already  described,  should  always  succeed,  the 
lethal  power  of  the  two  agents  combined  is  greater  than  that  of 
either  alone.  If  the  lethal  effects  be  omitted  from  consideration, 
we  find  that  the  experiments  on  animals  are  of  great  value  in  inter- 
preting the  antagonism  of  these  agents  on  man ;  for  they  serve  to 
show,  not  only  the  nature  of  the  antagonism,  but  the  method  of  its 
production.  These  experiments  demonstrate  that  morphia  and 
atropia  are  antagonistic  on  the  pupil,  on  the  action  of  the  heart, 
and  on  the  movements  of  respiration. 

We  are  now  prepared  to  undertake  to  investigate  the  nature  of 
the  antagonism  as  it  occurs  in  man.  To  proceed  from  the  known 
to  the  supposed,  we  must  first  form  a  definite  conception  of  the 
physiological  action  of  each.  What  effect  has  morphia,  what  effect 
has  atropia,  on  the  organism  of  man  ?  In  what  respects  do  they 
agree,  in  what  respect  do  they  differ  in  their  action  ?  The  action  of 
each  must  be  studied  in  respect  to  full  and  lethal  doses.  When  a 
full  dose  of  opium  is  administered,  drowsiness — in  some  subjects  an 
obstinate  wakefulness — comes  on  ;  the  pupil  contracts;  the  mouth, 


36  PHYSIOLOGICAL    ANTAGONISM. 

tongue,  and  throat  become  dry  ;  the  appetite  is  lost ;  constipation 
occurs  in  consequence  of  diminished  secretion  and  lessened  power 
in  the  muscular  layer  of  the  bowel ;  the  action  of  the  heart  slows 
and  declines  in  force ;  the  respirations  diminish  in  number  and 
depth ;  the  urine  is  passed  slowly  and  with  some  difficulty,  and  is 
scanty ;  and  the  skin  is  covered  with  a  copious  perspiration.  When 
a  lethal  or  toxic  dose  is  swallowed,  all  of  these  effects  are  intensi- 
fied ;  the  individual  passes  into  a  condition  of  stupor,  which  more 
or  less  quickly  deepens  into  coma,  from  which  no  form  of  irritation 
can  rouse  him  ;  the  pupils  contract  to  the  size  of  a  pin's  point,  and 
the  conjunctivas  are  insensible  to  irritation ;  no  reflex  movements 
are  excited  by  touching  the  cornea  or  by  titillating  the  fauces  ;  the 
respiration  is  slow,  descending  to  six,  to  four,  even  to  two  in  a  min- 
ute, and  is  stertorous  and  shallow ;  the  pulse  is  slow,  weak,  and 
irregular,  or  very  rapid,  irregular,  and  weak ;  the  skin  is  covered 
with  an  abundant  cold  sweat ;  the  countenance  is  pale  and  sunken, 
sometimes  blue  with  cyanosis  or  livid ;  the  ears  are  purplish,  and 
the  neck,  posteriorly,  bluish-black  from  ecchymosis;  and  the  extrem- 
ities, as  well  as  the  skin  generally,  are  cold  and  clammy.  Death 
ensues  by  failure  of  respiration. 

When  a  full  dose  of  belladonna  is  taken,  the  mouth  and  lips 
quickly  become  dry,  and  swallowing  is  difficult ;  the  head  feels  full, 
and  there  are  vertigo,  tinnitus  aurium,  and  flying  pains,  frequently 
severe  headache ;  the  mind  is  excited,  speech  rapid  and  voluble,  and 
there  occur  hallucinations — a  busy  delirium,  in  which  the  individ- 
ual is  engaged  in  his  usual  occupation — the  tailor  crosses  his  legs 
and  goes  through  the  motion  of  sewing ;  a  carpenter  appears  to  be 
driving  the  plane  or  handling  the  saw;  others  are  boisterous  and 
quarrelsome,  and  fall  to  fighting  and  struggling,  etc. ;  the  pupils 
are  widely  dilated ;  the  action  of  the  heart  is  rapid — the  pulse,  at 
first  firm,  afterward  is  weaker,  and  the  arterial  tension,  at  first 
raised,  declines  subsequently  below  normal ;  the  respirations  are 
quickened  ;  the  bowels  are  apt  to  be  relaxed  ;  the  urine  is  voided 
slowly  and  with  difficulty;  the  gait  is  unsteady  from  muscular 
incoordination,  and  the  muscular  system  is  weakened ;  the  skin  is 
dry  and  warm,  the  face  is  flushed,  and  often  covered  with  a  scarlet 
efflorescence,  etc.  When  a  lethal  or  toxic  dose  is  taken,  the  symp- 
toms just  mentioned  are  increased  in  all  directions ;  a  sudden  vertigo 
overpowers  the  voluntary  movements,  vision  quickly  grows  dim  and 
uncertain,  with  the  extreme  dilatation  of  the  pupil  ;  delirium  fol- 
lows quickly  and  is  occupied  with  ordinary  employments,  with  talk- 


OPIUM   AND    BELLADONNA.  37 

ing,  visiting,  sewing,  or  with  angry  controversy  and  struggling ; 
but  this  stage  of  hallucinations,  which,  when  non-lethal  but  large 
doses  are  taken,  is  protracted,  is  comparatively  short,  and  is  suc- 
ceeded by  coma,  or  there  come  on,  in  the  midst  of  excited  delirium, 
snatches  of  stupor,  but  presently  the  unconsciousness  becomes  pro- 
found ;  the  pupils  dilate  until  no  rim  of  the  iris  is  visible ;  the 
mouth  is  utterly  devoid  of  moisture,  and  the  tongue,  shrunken  and 
dry  as  a  bone,  lies  in  the  bottom  of  the  mouth  motionless  ;  the  flush 
of  the  face  is  succeeded  by  a  deathly  pallor  ;  the  pulse  becomes  very 
rapid,  and  the  respiration  is  hurried  ;  the  temperature  of  the  body 
rises,  but  the  increased  tension  of  the  arterial  system  is  succeeded 
by  paresis  of  the  vessels,  the  pulse  becoming  weak  and  fluttering  ; 
and  death  results  from  the  failure  of  the  heart  and  lungs. 

A  comparison  of  the  actions  on  man  shows  that  opium  and  bella- 
donna act  oppositely,  or  in  an  opposite  manner,  on  the  brainy  on  the 
pupil,  on  the  circulation,  on  the  lungs,  on  the  stomach,  and  on 
the  skin.  Opium,  with  the  exceptions  named,  causes  somnolence 
and  stupor ;  belladonna,  excitement,  hallucinations,  and  delirium. 
When  administered  jointly  and  in  the  proper  proportions,  sopor, 
closely  approximating  natural  sleep,  is  the  result.  This  was  well 
exhibited  in  the  case  of  Dr.  Legg,*  whose  patient,  a  boy  of  five 
years,  drank  by  mistake  a  mixture  of  equal  parts  of  liniment  of 
opium  and  liniment  of  belladonna.  The  effects  of  the  belladonna, 
owing  to  its  more  rapid  action,  first  dominated  the  situation,  when 
there  was  delirium  with  hallucinations,  the  boy  driving  sheep,  and 
picking  up  money  from  the  bed  ;  but  then  drowsiness  supervened, 
and  heavy  sleep,  when  he  was  not  forced  awake  and  kept  walking. 
The  violence  of  this  ambulatory  treatment  was  wholly  unnecessary, 
and  indeed  injurious,  for,  if  he  had  been  permitted  to  sleep,  the 
antagonism  on  the  respiration  and  circulation  would  have  sufficed  to 
save  life.  Facts  of  the  same  kind  were  observed  in  a  case  jointly 
cared  for  by  Dr.  Mussey,  of  Cincinnati,  and  myself.  A  boy  of  eight 
years,  the  son  of  a  physician  of  Cincinnati,  was  given  internally  by 
mistake  an  anodyne  application  for  earache,  containing  two  grains 
of  morphia  and  one  grain  and  a  half  of  atropia.  When  the  toxic 
symptoms  were  well  advanced,  the  mistake  was  discovered,  and  Dr. 
Mussey  and  myself  were  summoned.  We  found  the  pupils  fully 
dilated,  the  face  flushed,  and  an  active  delirium,  in  which  the  boy 
fought  and  struggled  violently  against  imaginary  enemies.  After 

*  "  Med.  Times  and  Gaz.,"  Nov.  3,  1866,  p.  474. 


38  PHYSIOLOGICAL    ANTAGONISM. 

an  hour  or  two  of  this  excitement,  a  soporose  state  came  on,  and  was 
very  profound  for  a  number  of  hours.  As,  however,  the  respira- 
tion was  full,  strong,  and  rhythmical,  the  pulse  regular  and  of  good 
volume,  we  decided  to  await  the  result  of  the  antagonism.  Dr. 
Mussey  had  published  one  of  the  first  cases  of  opium  poisoning 
illustrating  the  antagonistic  action  of  belladonna,  and  I  had  seen 
several  cases,  so  that  we  were  perfectly  agreed  as  to  the  proper 
course,  and  the  result  justified  our  decision.  Another  case,  in  which 
the  simultaneous  administration  of  opium  and  belladonna  was  due 
to  accident,  was  reported  by  Dr.  Cotter.*  A  young  lady  swallowed 
a  liniment  composed  of  opium  and  belladonna,  the  amount  taken 
being  equivalent  to  twenty-five  grains  of  the  extract  of  belladonna 
and  twelve  grains  of  opium.  At  first,  the  symptoms  of  belladonna 
poisoning  were  largely  in  excess ;  after  some  hours,  she  appeared 
like  one  helplessly  drunk,  and  was  so  drowsy  as  to  be  kept  awake 
with  great  difficulty ;  then  another  period  of  excitement  came  on, 
and  this  was  followed  by  a  period  of  profound  sleep,  from  which  she 
awoke  relieved.  Such  are  the  facts  as  taught  us  by  these  accidental 
experiments  on  man.  What  is  the  clinical  experience  available  for 
further  study  of  the  problem  ? 

As  a  result  of  large  observation  and  experience  of  the  effects  of 
these  agents  on  man,  Drs.  Mitchell,  Morehouse,  and  Keen  conclude 
that  "  the  headache  and  phantasms  of  atropia  are  certainly  thus 
controlled  [i.  e.,  by  morphia],  as  well  as  the  partial  deafness  and 
visual  defects  which  in  high  doses  it  occasions.  On  the  other  hand, 
when  morphia  has  been  fully  used,  the  drowsiness  and  stupor  which 
are  the  best  tests  of  its  power  disappear  before  the  influence  of 
atropia.  .  .  .  Perhaps  the  most  peculiar  cerebral  symptom  of  atro- 
pia is  its  tendency  to  cause  phantasms  and  illusions.  We  found 
under  doses  of  -fa  of  a  grain  these  were  common,  and  in  some  men 
could  always  be  brought  on.  Usually  they  were  absent  so  long  as 
the  eyes  remained  open,  but  arose  at  once  on  closing  them.  This 
condition  was  singularly  subdued  by  morphia.  Drowsiness  caused 
by  morphia  was  as  surely  lessened  or  destroyed  by  the  counter 
agency  of  atropia;  and,  in  fact,  atropia  given  alone  and  in  full 
doses  is  very  apt  to  cause  a  restless  night  to  follow,  so  that  it  is 
assuredly  in  no  sense  a  hypnotic." 

Harley  strongly  insists  on  the  modifying  influence  of  morphia 
over  the  cerebral  effects  of  atropia.  "  The  influence  of  opium  in 

*  "  Am.  Jour,  of  the  Med.  Sci.,"  vol.  1,  p.  67,  et  seq. 


OPIUM    AND    BELLADONNA.  39 

converting  the  insomnia  of  belladonna  into  sleep,  and  the  influence 
of  belladonna  in  determining,  not  only  sleep  but  narcotism  in  indi- 
viduals under  the  influence  of  opium,  are  illustrated  in  several  ex- 
amples. Some  of  the  cases,"  he  further  says,  "  serve  to  give  greater 
force  to  these  observations,  and  teach  us  .that  we  must  be  careful 
how  we  employ  opium  as  a  means  of  converting  the  restlessness  and 
insomnia  following  excessive  doses  of  belladonna  into  quiet  sleep." 
Harley,  strangely  enough,  does  not  regard  these  different  cerebral 
effects  as  due  to  an  antagonistic  action,  but  as  synergistic.  It  is, 
nevertheless,  evident  enough  that  his  observations  are  confirmatory 
of  those  of  Mitchell,  Morehouse,  and  Keen,  who  state  with  more 
precision  the  exact  features  of  the  reciprocal  influence.  In  fact,  at 
the  present  time  professional  opinion  is  no  longer  divided  on  this 
point,  and  morphia  and  atropia,  and  opium  and  belladonna,  are 
constantly  prescribed  together  to  secure  an  hypnotic  effect,  not  at- 
tainable by  the  exhibition  of  either  remedy  alone.  Clinical  expe- 
rience on  man  has  been  confirmed  by  observations  on  animals,  so 
far  as  the  facts  are  applicable.  Thus,  Erlenmayer*  shows  that  the 
exciting  effect  of  atropia  on  the  brain  is  lessened  by  the  narcosis  of 
morphia.  Harley 's  experiments  on  dogs  were  similar  in  results: 
"  The  cerebral  effects  of  atropia  are,"  he  says,  "intensified  and  pro- 
longed— the  insomnia  which  results  from  excessive  doses  is  con- 
verted into  narcotism,  or  a  mixture  of  narcotism  and  delirium." 
Heubach,t  whose  researches  were  carried  on  in  Binz's  laboratory, 
was  led  to  similar  conclusions.  Obviously,  the  actions  of  such 
agents  on  the  brains  of  animals  can  be  compared  only  according  to 
the  extent  of  development,  for,  the  brain  of  man  being  more  com- 
plex in  structure  and  more  highly  specialized,  must  be  affected  both 
with  less  severity  and  in  a  greater  variety  of  manifestations.  In 
animals  the  effect  of  the  narcotic  is  necessarily  limited  to  the  ce- 
phalic organs  possessed  by  them,  whereas  in  man,  not  only  to  those, 
but  to  the  higher  special  organs  he  is  possessed  of,  is  the  influence 
distributed.  In  animals  the  narcotic  more  affects  the  motor  centers 
and  the  centers  of  respiration  and  circulation,  while  in  man  its  effects 
are  exerted  not  only  upon  these  centers,  but  upon  the  higher  cen- 
ters and  upon  the  mental  sphere.  Do  we  not  have  in  this  difference 
in  development  the  reason  of  the  much  greater  toxic  .power  in  ani- 
mals of  morphia  and  atropia  when  administered  simultaneously  ? 

*  "  Berlin,  klin.  Woch.,"  loc.  cit. 

f  "Arch.  f.  experiment.  Pathol.  u.  Pharmakol,"  1878,  Band  viii,  p.  31.     "  Antagonis- 
mus  zwischen  Morphin  u.  Atropin." 


40  PHYSIOLOGICAL   ANTAGONISM. 

Bernard*  has  signalized  this  important  point  in  his  introduction  to 
the  study  of  experimental  medicine.  After  declaring  that  observa- 
tions on  animals,  in  respect  to  the  functions  of  the  cerebro-spinal 
nerves,  and  the  vaso-motors  and  secretors  of  the  sympathetic,  and 
on  circulation  and  digestion,  hygiene  and  toxicology,  are  perfectly 
and  at  all  points  applicable  to  man,  he  indicates  conditions  under 
which  the  observations  on  animals  are  not  thus  applicable.  For 
example :  "  From  the  physiological  point  of  view,  the  experimental 
study  of  the  organs  of  sense  and  of  the  cerebral  functions  must  be 
made  on  man  necessarily,  because  on  the  one  hand  man  is  above 
the  animals  in  respect  to  those  faculties  of  which  they  are  not  pos- 
sessed, and,  on  the  other,  animals  are  unable  to  indicate  the  nature 
of  those  sensations  of  which  they  may  become  conscious." 

My  conclusion,  after  the  examination  of  the  experimental  and 
clinical  evidence,  therefore,  is,  that,  as  respects  the  brain,  opium  and 
belladonna  exert  opposing  actions.  The  illusions,  hallucinations, 
and  busy  delirium  caused  by  belladonna  are  counteracted  by  opium. 
The  result  of  their  conjoined  action  is  sopor,  deepening  into  coma 
when  the  quantity  of  both  is  large.  When  administered  simultane- 
ously, if  the  effects  of  atropia  preponderate,  there  will  occur  periods 
of  excitement  and  delirium,  interspersed  with  relatively  shorter 
periods  of  sopor  and  coma.  The  more  decidedly  opium  preponder- 
ates, the  less  there  will  be  of  delirium,  and  the  more  of  sopor. 
When  opium  is  in  excess,  the  tendency  is  to  coma  and  stertorous 
breathing,  after  a  period  of  sopor. 

There  are  some  highly  important  points  in  regard  to  the  an- 
tagonistic action  of  morphia  and  atropia  on  the  pupil.  Graves,  as  is 
well  known,  first  proposed  to  make  use  of  this  antagonism  as  a 
guide  to  treatment.  There  can  be  no  doubt  that  this  antagonism 
exists — that  opium  contracts  and  belladonna  dilates  the  pupil ; 
opium  weakening  and  belladonna  stimulating  the  radiating  fibers 
of  the  iris.  There  are,  however,  occasional  exceptions.  As  the 
state  of  the  pupil  is  usually  regarded  as  a  guide  to  the  use  of  the 
antagonist  in  cases  of  poisoning,  it  becomes  in  a  high  degree  impor- 
tant to  know  if  this  indication  can  or  can  not  be  depended  on,  and 
to  what  extent.  In  Case  XIY  of  the  list  of  unsuccessful  cases,  we 
find  that  a  very  large  quantity  of  morphia  was  given  to  counteract 
the  effects  of  some  belladonna  liniment  taken  by  accident,  and  that, 
notwithstanding  the  apparent  preponderance  in  the  action  of  the 

*  "  Introduction  &  1'Etude  de  la  M6decine  ExpSrimentelle."    Paris,  1865,  p.  219. 


OPIUM    AND    BELLADONNA.  41 

morphia,  the  pupil  continued  dilated.  In  one  of  the  successful 
cases  of  joint  administration  of  opium  and  belladonna,  in  which  the 
symptoms  produced  by  the  latter  much  preponderated,  the  pupil 
was  minutely  contracted.  It  has  been  observed  occasionally,  in 
cases  of  opium  poisoning,  that  at  a  certain  stage  in  the  narcosis  the 
pupil  dilated.  On  the  other  hand,  in  profound  belladonna  narcosis, 
the  largely  dilated  pupil  has  suddenly  contracted  in  some  occasional 
cases.  There  are  exceptional  manifestations,  it  is  true,  but,  as  there 
are  two  examples  in  120  cases,  the  value  of  the  indication  afforded 
by  the  state  of  the  pupil  is  correspondingly  weakened.  The  an- 
tagonism between  morphia  and  atropia  may  be  exerted  without  the 
contraction  caused  by  the  former,  or  the  dilatation  by  the  latter, 
being  entirely  overcome.  No  fewer  than  twenty  cases  illustrate 
this  proposition.  The  rate  at  which  these  agents  act  on  the  pupil 
varies  greatly.  Atropia  acts  both  more  promptly  and  for  a  much 
longer  time.  Atropia  has,  also,  a  more  powerful  action — for,  of  the 
twenty  cases  which  show  that  the  size  of  the  pupil  may  not  be  much 
affected  by  the  antagonist,  sixteen  were  examples  of  preponderating 
dilatation.  From  these  facts,  it  must  be  concluded  that  the  state  of 
the  pupil  can  not  always  serve  as  a  guide  for  the  further  adminis- 
tration of  the  antagonist. 

The  next  point  for  consideration  is — the  antagonistic  influence 
of  opium  and  belladonna  on  the  heart.  That  opium,  in  full  doses, 
acting  alone,  slows  the  heart,  and  that  belladonna  quickens  it,  are 
unquestionable  facts.  Observers  are  by  ixo  means  agreed  as  to  the 
influence  reciprocally  exerted  by  these  agents  when  administered 
simultaneously.  Mitchell,  Morehouse,  and  Keen  find  that  "  mor- 
phia has  no  power  to  prevent  atropia  thus  influencing  the  pulse,  so 
that  as  regards  the  circulation  they  do  not  counteract  one  another." 
Harley  maintains  that  morphia,  here  as  elsewhere,  increases  the 
effect  of  atropia.  "  If,  however,"  he  says,  "  the  dose  of  atropia  is 
small,  and  the  morphia  produce  considerable  derangement  of  the 
vagus,  the  rapidity  of  pulse  is  not  greater  than  when  the  atropia  is 
administered  alone.  In  rny  own  observations  I  have  invariably  seen 
that  the  acceleration  of  pulse  produced  by  atropia  is  lessened  by 
morphia,  and  vice  versa,  and  this  is  the  conclusion  derived  from  a 
study  of  the  reported  cases  of  poisoning.  The  effect  of  the  atropia, 
however,  preponderates.  The  result  of  the  combined  effect  is  not 
the  mean  of  the  two,  but  is  nearer  the  standard  of  atropia  than  of 
morphia.  As  wakefulness  and  active  delirium  increase  the  pulse 
rate,  and  stupor  with  absolute  repose  lessens  it,  these  factors  must 


42  PHYSIOLOGICAL    ANTAGONISM. 

also  be  considered  in  estimating  the  relative  share  of  opium  and 
belladonna  in  the  result.  The  experiments  on  animals  have  usually 
demonstrated  an  antagonistic  action  as  regards  the  heart."  Harley's 
experiments  on  dogs  certainly  show  that  the  accelerating  effect  of 
atropia  on  the  heart  is  remarkably  lessened  by  combination  with 
morphia.  In  the  careful  experiments  of  Heubach,  the  same  result 
is  shown ;  the  increased  pulsations  caused  by  atropia  are  diminished 
by  morphia,  but  the  general  level  of  effect  is  above  the  mean  consid- 
erably. We  must,  therefore,  conclude  that  the  effects  of  morphia 
are  antagonistic  to  those  of  atropia  on  the  heart  to  a  limited  extent, 
but  that  the  effects  of  atropia  preponderate,  and,  hence,  the  result 
of  the  combined  effects  is  a  rate  of  movement  greater  than  the 
mean. 

"Without  doubt,  the  most  important  point  in  the  whole  range  of 
the  antagonism  of  morphia  and  atropia  is  the  opposed  action  on 
the  respiratory  function.  Less  difference  of  opinion  exists  on  this 
than  on  any  other  point  connected  with  the  subject.  In  general 
terms,  it  may  be  said  that  opium  is  a  respiratory  depressant,  and 
atropia  a  respiratory  stimulant.  The  cause  of  death  in  opium  nar- 
cosis is  failure  of  respiration,  the  action  of  the  heart  ceasing  after 
respiration.  Atropia  counteracts  this  tendency,  and  maintains  the 
activity  of  the  respiratory  function.  All  the  cases  of  poisoning 
teach  this  lesson.  As  the  opium  narcosis  deepens,  the  respiratory 
acts  become  less  and  less  frequent  and  more  arid  more  shallow ;  the 
quantity  of  oxygen  admitted  to  the  blood  lessens,  and  the  oxidation 
processes  decline ;  the  surface  becomes  cold,  and,  carbonic  acid 
accumulating,  carbonic-acid  narcosis  is  added  to  the  toxic  coma. 
Atropia  counterbalances  these  effects  by  raising  the  number  and 
increasing  the  depth  of  the  respiratory  acts,  hence  more  oxygen  is 
admitted  to  the  blood,  the  chemical  interchanges  are  more  exten- 
sive and  speedy,  and  excretion  is  facilitated.  The  improvement  is 
represented  by  a  flushed  face,  a  warm  and  dry  skin,  and  a  more 
active  circulation  generally. 

Atropia  proves  fatal  by  exhausting  the  irritability  of  the  motor 
ganglia  of  the  heart  and  of  the  general  vaso-motor  system,  and  also 
of  the  respiratory  centers.  Morphia,  by  lessening  the  work  of  the 
heart  and  of  the  lungs,  opposes  these  effects  of  atropia.  The  facts 
presented  in  the  120  cases  of  poisoning  generally  support  this  view 
of  the  antagonism.  In  some  of  the  cases,  it  is  true,  the  narcosis 
was  too  profound  to  permit  any  new  impression  to  be  made  ;  but, 
in  those  suitable  for  the  action  of  the  antagonist,  nothing  could  be 


OPIUM   AND    BELLADONNA.  43 

more  striking  than  its  favorable  influence  on  the  respiration.  Dr. 
Johnston,  of  Shanghai,  whose  experience  of  opium  poisoning  has 
reached  to  hundreds  of  cases,  says  that  the  effect  of  the  atropia  is 
simply  marvelous  in  stimulating  the  respiratory  function  and  remov- 
ing the  carbonic-acid  narcosis.  In  the  fatal  case  of  atropia  poison- 
ing narrated  by  Dr.  Gross,  the  injection  of  morphia  induced  stertor. 
I  have  already  suggested  that  the  more  gradual  introduction  of  the 
morphia  influence  would  have  prevented  this  accident,  which  seems 
to  have  been  an  idiosyncrasy,  rather.  In  a  case  narrated  by  Dr. 
Fothergill,*  the  influence  of  the  antagonist  on  the  respiratory  func- 
tion is  most  conspicuous.  A  woman  had  taken,  at  11  A.  M.,  lauda- 
num containing  from  12  to  17  grains  of  opium.  At  2  p.  M.  the 
respiration  was  almost  gone,  but  the  pulse,  though  small,  was  rhyth- 
mical and  regular.  One  grain  of  sulphate  of  atropia  was  then 
injected  subcutaneously.  In  a  half  hour  the  respiration  was  becom- 
ing well  established,  and,  in  an  hour  and  a  half  after  the  injection, 
was  going  on  steadily,  13  to  the  minute,  and  long  and  deep.  No 
further  use  of  the  antagonist  was  necessary  to  overcome  the  effects 
of  the  poison.  It  is  probable,  indeed,  that  the  quantity  of  atropia 
used  was  rather  in  excess,  as  an  emetic  had  caused  the  discharge  of 
some  opium,  and  the  subsequent  account  shows  a  preponderating 
action  of  atropia.  An  equally  instructive  case,  as  showing  the 
power  of  atropia  to  overcome  the  respiratory  depression  caused  by 
morphia,  is  narrated  by  Dr.  McGee.f  A  stout,  muscular  man  ot 
40  years  swallowed  30  grains  of  opium  in  10  or  12  ounces  of  whisky. 
He  became  profoundly  comatose.  In  two  hours  an  eighth  of  a 
grain  of  atropia  was  injected,  and,  this  having  no  effect,  in  a  half 
an  hour  the  same  quantity  was  repeated.  The  respirations  were 
then  nearly  suspended,  the  face  being  livid,  but  under  the  influence 
of  the  atropia  the  respirations  increased  greatly ;  the  pulse  rose  to 
140,  the  pupils  became  widely  dilated,  and  consciousness  was  so  far 
restored  that  the  patient  could  be  roused.  He  then  slept  profoundly 
for  a  number  of  hours,  but  his  pulse  continued  at  81,  with  the  res- 
pirations full  and  deep,  and  Dr.  McG-ee,  wisely  trusting  to  the 
antagonistic  action,  did  not  exhaust  his  patient  by  ambulation,  fla- 
gellation, artificial  respiration,  and  other  ingenious  devices  for  keep- 
ing awake  those  who  need  the  restorative  effects  of  sleep  and  quiet. 
I  might  narrate  many  examples  from  the  collection  of  cases  made 
for  this  study,  showing  the  importance  of  the  antagonism  exerted 

*  "  The  Antagonism  of  Therapeutic  Agents."     Philadelphia :  H.  C.  Lea,  1878,  p.  132. 
f  "Am.  Jour,  of  the  Med.  Sci.,"  July,  1869,  p.  282. 


44  PHYSIOLOGICAL    ANTAGONISM. 

on  the  respiratory  function.  There  is  no  difference  in  the  lesson 
taught  us  in  the  cases  of  opium  narcosis.  The  cases  of  atropia  poi- 
soning treated  by  morphia  are  not  less  instructive.  Various  exam- 
ples come  to  us  with  the  authority  of  such  names  as  Graefe,* 
Schmidt,t  Fronmuller,J  Cohn,§  and  others,  occurring  in  ophthal- 
mic practice.  Some  of  these  were  probably  not  lethal,  although 
characteristic  and  violent  symptoms  were  produced ;  yet  the  antag- 
onistic action  of  the  morphia  was  not  less  conspicuously  displayed. 

If  we  now  pass  from  the  clinical  evidence  to  the  results  of  experi- 
mental research  on  man  and  on  animals,  we  are  greatly  surprised 
with  the  differences  in  the  conclusions  drawn.  Mitchell,  More- 
house,  and  Keen  conclude  that  "  the  influence  of  atropia  on  the 
pulse  and  respiration  is  in  no  way  altered  by  the  use  of  full  doses 
of  morphia,  so  that  in  this  particular  their  supposed  antagonism 
does  not  exist."  In  some  experiments  of  my  own,  made  on  a  med- 
ical student,  I  found  that  morphia  modified  to  a  considerable  extent 
the  effects  of  atropia  on  the  pulse  and  respiration — a  fact  clearly 
exhibited  in  the  graphic  representation  of  the  results. ||  Harley  ex- 
presses himself  with  decision  against  the  supposed  antagonism  of 
these  agents  on  the  respiratory  function,  but  he  indicates  conditions 
under  which  they  may  be  used  in  opposition  with  advantage — a 
singular  contradiction  between  his  facts  and  his  opinions.  "  Bella- 
donna is  powerless  to  obviate  the  chief  danger  in  opium  poisoning, 
viz.,  the  depression  in  the  respiratory  function."  But,  in  another 
place,  he  says,  "in  the  treatment  of  belladonna  poisoning,  our 
efforts  must  be  directed  to  sustain  the  breathing.  Opium  must  be 
used,  not  as  an  antidote,  but  as  a  means  of  calming  the  nervous  agi- 
tation when  it  is  excessive,"  etc.  It  is  impossible  to  find  any  mean- 
ing in  such  explanations.  Again,  he  says,  "  when  the  heart  shows 
indications  of  failing  power,  the  subcutaneous  injection  of  -fa  grain 
of  sulphate  of  atropia,  at  intervals  of  two  hours,  must  be  prac- 
ticed." The  facts  of  Dr.  Harley  admit  of  very  different  interpre- 
tations from  those  which  he  has  advanced ;  they  prove  that  atropia 
exerts  a  distinct  stimulant  action  on  the  respiratory  organs,  and  are 
in  conformity  with  clinical  experience.  We  may  now  regard  it  as 
settled  that  atropia  antagonizes  the  depression  caused  by  morphia  on 
the  respiratory  function,  notwithstanding  the  adverse  opinions  just 
quoted. 

*  "Schmidt's  Jahrbiicher,"  vol.  cxxv,  p.  350.         \  Ibid.,  vol.  cxxiv,  p.  167. 
\  Ibid.,  vol.  cxxvi,  p.  282.  §  "Berlin,  klin.  Woch.,"  11,  16,  1866. 

J  "Manual  of  Hypodermic  Medication,"  3d  ed.,  Philadelphia,  1879. 


OPIUM    AND   BELLADONNA.  45 

The  antagonistic  action  of  atropia  and  morphia  is  further  exhib- 
ited in  the  control  of  the  former  over  the  nausea,  depression,  and 
actual  syncope  caused  by  the  latter.  This  antagonism  is  exhibited 
in  ordinary  medicinal  doses,  and  clinical  experience  justifies  the 
remark  of  Harley,  that  morphia  should  not  be  administered  alouey 
unless  its  action  on  the  subject  is  known,  but  always  with  atropia. 
The  explanation  of  the  utility  of  atropia  in  preventing  the  nausea 
and  depression  caused  by  morphia  consists  in  the  counterbalancing 
action  of  these  agents  on  the  cerebrum.  While  the  depression — 
ofttimes  the  syncope — is  thus  prevented,  the  nausea  may  occur,  for 
atropia,  also,  excites  nausea  in  some  subjects.  The  coldness  of  the 
surface  and  the  clammy  sweat  caused  by  morphia  are  removed  by 
atropia.  The  importance  of  this  fact  is  considerable.  The  first 
effect  of  morphia  is  to  raise  the  arterial  tension  and  to  energize  the 
cardiac  movements,  but  this  is  followed  by  decline  in  the  tension 
and  by  slowing  of  the  movements.  The  peripheral  vessels  become 
relaxed,  and  the  blood  current  becomes  slow;  the  sweat  glands  act 
freely,  and  the  functional  interchanges  between  the  blood  and  tis- 
sues are  suspended.  The  action  of  atropia  brings  about  an  import- 
ant change ;  the  peripheral  vessels  contracting  in  their  vermicular 
manner,  and  more  blood  being  received  from  the  heart,  the  surface 
grows  warm  and  dry,  and  the  function  of  metamorphosis  of  tissue 
is  resumed.  The  effect  of  this  resumption  of  activity  at  the  pe- 
riphery, on  the  condition  of  the  cerebrum,  is  only  less  important 
than  the  renewal  of  hsematosis  at  the  lungs. 

Atropia  stimulates  the  action  of  the  kidneys  somewhat,  and 
morphia  checks  the  flow  of  urine.  They  both  act  to  render  the 
emission  of  urine  more  difficult,  but  it  is  an  error  to  suppose  that 
they  act  in  the  same  way.  Morphia  dulls  the  sensibility  of  the  mu- 
cous membrane,  and  diminishes  the  contractile  energy  of  the  mus- 
cular coat  of  the  bladder;  atropia  stimulates  the  sphincter  to  more 
energetic  contraction,  so  that  the  voluntary  efforts  at  relaxation  are 
opposed. 

Having  now  indicated  the  points  of  antagonism,  and  examined 
into  the  opinions  for  and  against  the  belief  in  its  existence,  we  are 
prepared  to  ascertain  how  a  lethal  dose  of  the  one  can  overcome 
the  effects  of  a  corresponding  dose  of  the  other  agent.  It  is  evi- 
dent that  very  rarely  is  a  lethal  dose  of  one  agent  counterbalanced 
by  the  other  in  animals.  The  reason  apparently  is  the  difference 
in  the  extent  and  variety  of  the  cerebral  structures  in  man,  as  com- 
pared with  the  interior  animals.  The  physiological  actions  are  the 


46  PHYSIOLOGICAL    ANTAGONISM. 

same  in  animals  as  in  man,  except  the  difference  in  degree,  to  em- 
ploy the  words  of  the  illustrious  Bernard,  but,  when  we  reach  the 
brain,  we  tind  that  in  animals  the  force  of  the  poison  is  expended 
on  a  few  comparatively  simple  organs,  whereas  in  man  it  is  diffused 
over  much  more  extensive  and  complicated  structures. 

Experience  has  demonstrated  that  the  quantity  of  poison  which 
can  be  antagonized  successfully,  and  a  fatal  result  averted,  is  com- 
paratively limited.  Yery  considerable  quantities,  as  we  have  seen, 
were  taken  in  some  of  the  successful  cases,  but  they  did  not  exceed 
a  certain  limit,  and  the  stomach-pump  and  emetics  were  freely  used, 
so  that  the  actual  amount  entering  the  blood  was  far  less  than  that 
taken  into  the  stomach.  What  disposition  of  the  poison  is  effected  ? 
There  is  no  chemical  union  of  the  antagonist,  to  destroy  the  toxic 
power.  It  is  simply  opposed  until  elimination  is  accomplished. 
The  tendency  to  destroy  life  by  overwhelming  the  functions  of  par- 
ticular organs  is  opposed  and  held  in  check,  and  gradually  the 
poison  is  eliminated.  Furthermore,  the  separation  of  the  poison 
from  the  blood  and  its  excretion  by  the  usual  channels  are  greatly 
promoted  by  the  action  of  the  antagonist  in  maintaining  the  func- 
tional activity  of  the  organs  depressed  by  the  poison.  The  rate  of 
elimination  and  the  means  of  promoting  it  become,  therefore,  im- 
portant elements  in  the  management  of  these  cases,  and,  I  may  also 
add,  are  usually  wholly  neglected.  The  principal  route  of  excretion 
is  by  the  kidney,  but  the  skin  and  intestinal  canal,  also,  convey  off 
some  of  the  poison.  In  a  few  minutes  after  the  alkaloids  are  swal- 
lowed, traces  of  them  are  discoverable  in  the  urine.  Free  action  of 
the  kidneys  should  therefore  be  maintained  by  the  use  of  diluents. 
Another  practical  point  of  high  importance  is,  the  removal  of  the 
urine  as  fast  as  it  accumulates  in  the  bladder.  Brown-Sequard  has 
shown  that  absorption  of  alkaloids  takes  place  from  the  mucous 
membrane  of  the  bladder,  and  he  proposes  to  make  use  of  this  fact 
by  injecting  morphia  solutions  into  this  viscus.  It  is  probable  that 
alkaloids  contained  in  the  urine  may  diffuse  into  the  blood  again 
from  the  bladder.  The  action  of  the  bowels  should  be  free,  and 
the  skin  should  be  stimulated — in  fact,  all  the  channels  of  excretion 
should  be  kept  freely  at  work. 

No  absolute  rule  can  be  laid  down  as  to  the  quantity  of  the 
antagonist  to  be  used.  Taking  morphia  poisoning  as  the  type,  the 
quantity  of  atropia  must  be  determined  by  the  effects.  What  are 
the  guides  ?  The  pupils  ?  No.  For,  although  they  may  react  in 
the  usual  way  to  the  antagonist,  it  must  be  remembered  that  the 


OPIUM    AND    BELLADONNA. 

action  of  atropia  preponderates,  and  in  some  instances  they  do  not 
react  normally.  The'  true  guides  are  the  state  of  the  respiration 
and  that  of  the  circulation.  If  the  breathing  is  deep  and  rhythmi- 
cal, and  the  pulse  is  full  and  strong,  the  state  of  the  pupil  and  the 
depth  of  the  narcotism  are  of  little  moment.  When  the  amount  of 
the  antagonist  administered  suffices  to  establish  the  respiration  and 
circulation  in  their  proper  condition,  the  quantity  is  sufficient, 
whether  or  not  it  may  be  theoretically.  As  a  rule,  it  is  better  to 
give  the  antagonist  in  small  quantity,  frequently  repeated,  until  the 
amount  required  has  been  given.  Large  doses,  as  is  evident  in 
some  of  the  cases,  produce  unpleasant  effects,  and  may  be  in  excess 
of  the  real  requirements.  In  some  actual  trials,  I  found  that 
J^-  grain  of  atropia  was  about  equal  in  toxic  power  to  a  grain 
of  morphia.  In  deciding  on  the  dose  of  the  antagonist,  the  amount 
of  the  poison  probably  eliminated  must  be  taken  into  considera- 
tion. 

Having  completed  the  survey  of  opium  and  belladonna,  I  sub- 
mit the  following  conclusions : 

Morphia  and  atropia  are  antagonistic  in  their  effects  on  the 
cerebrum,  and  the  result  of  the  antagonism  is  to  induce  sopor,  but 
this  deepens  into  coma  if  the  quantity  used  is  large,  and  hence  the 
opposition  does  not  extend  to  lethal  quantities. 

They  are  antagonistic  in  their  action  on  the  pupil,  but  this  effect 
is  not  constant,  owing  to  idiosyncrasy,  and  the  action  of  atropia 
preponderates  and  is  more  lasting. 

They  are  antagonistic  in  their  action  on  the  heart,  morphia 
slowing  and  atropia  increasing  the  rate  of  movement,  but  the  effect 
of  atropia  is  both  more  powerful  and  more  prolonged. 

They  are  antagonistic  in  their  action  on  respiration,  morphia 
slowing  and  atropia  increasing  the  respiratory  movements.  Ac- 
cordingly, morphia  diminishes  the  excretion  of  carbonic  acid,  and 
causes ,  carbonic-acid  narcosis ;  atropia  promotes  the  excretion  of 
carbonic  acid,  and  thus  helps  the  function  of  hsematosis. 

They  are  antagonistic  in  their  action  on  the  arterial  tension. 
Morphia,  after  tirst  raising,  greatly  depresses  the  arterial  tension, 
and  suspends  haematosis  by  slowing  the  heart  and  paralyzing  the 
arterioles.  Atropia  antagonizes  all  of  these  actions. 

Atropia  prevents  to  a  large  extent,  in  many  cases  entirely,  the 
depression,  coldness  of  the  surface,  cold  sweating,  and  cerebral  nau 
sea  caused  by  morphia. 

Morphia  and  atropia  are  antagonistic  in  their  action  on  the  kid- 


48  PHYSIOLOGICAL    ANTAGONISM. 

nejs,  the  former  diminishing,  the  latter  augmenting,  the  urinary- 
discharge.  They  differ  in  their  action  on  the  bladder,  morphia 
lowering  the  sensibility  of  the  mucous  membrane  and  weakening 
the  muscular  layer,  while  atropia  stimulates  the  sphincter.  They 
are  not  therefore  antagonistic  in  their  effect  on  the  bladder. 

In  therapeutics,  these  antagonisms  are  made  use  of  to  procure 
effects  not  attainable  by  either  drug  singly ;  to  avoid  unpleasant 
results  produced  by  each,  and  to  enhance  the  safety  of  their  ad- 
ministration in  full  doses.  The  whole  subject  affords  a  beautiful 
example  of  the  success  of  the  methods  employed  by  modern  phar- 
macological research  to  improve  our  knowledge  of  the  action  of  the 
oldest  remedies,  and  to  increase  the  safety,  certainty,  and  range  of 
their  applications  to  the  treatment  of  disease. 


LECTUKE  III. 

ANTAGONISM  OF  ATROPIA  AND  PHYSOSTIGMA ;  ATEOPIA  AND  PILOCAE- 
PIN  ;  ATEOPIA  AND  MUSCAEIA.  J  ATEOPIA  AND  QUINIA  *  ATEOPIA 
AND  BEOMAL  HYDEATE ;  AND  ATEOPIA  AND  ACONITINE. 

THE  next  investigation  of  the  antagonism  between  medicinal 
agents  is  concerned  with  the  opposition  of  actions  between  atropia 
and  physostigma,  or  Calabar  bean.  The  extract  and  the  active 
principle — eserine,  or,  as  it  is  sometimes  called,  physostigmine,  or 
calabarine — are  the  preparations  used  to  procure  the  physiological 
effects  of  physostigma. 

For  the  first  time,  in  1864,  Klein  wachter  treated  a  case  of  poi- 
soning by  atropia  by  the  internal  administration  of  physostigma,  the 
symptoms  being  relieved  to  a  great  extent.  In  1867  Bourneville,  in 
a  thesis  on  the  treatment  of  tetanus  by  physostigma,  related  a  single 
experiment  in  which  the  effects  produced  by  a  quantity  of  the  pow- 
dered kernel,  introduced  into  the  stomach  of  a  cabiai,  were  over- 
come by  the  subcutaneous  injection  of  atropia.  In  1868  I  made  a 
number  of  experiments  proving  the  existence  of  the  antagonism. 
The  most  important  research  was  that  of  Professor  Thomas  R. 
Eraser,  of  Edinburgh,  in  1869,  who  performed  a  great  variety  of 
experiments,  and  introduced  new  principles  for  the  guidance  of 
future  researches  of  the  same  kind.*  This  investigation  was  fol- 
lowed by  the  report  of  the  Committee  of  the  British  Medical  Asso- 
ciation, Dr.  J.  Hughes  Bennett,  Chairman.f 

Before  proceeding  to  the  analysis  of  the  published  facts  and  ex- 
periments, we  must  have  a  definite  conception  of  the  actions  of  the 
two  agents.  In  what  respect  do  atropia  and  physostigma  differ  ? 
I  have  already  described  the  deliriant  effect  of  atropia,  its  power  to 

*  "  On  the  Antagonism  between  the  Actions  of  Physostigma  and  Atropia."     From 
the  "Trans,  of  the  Roy.  Soc.  of  Edinburgh,"  vol.  xxvi. 
f  "  Brit.  Med.  Jour."  for  1874. 


50  PHYSIOLOGICAL    ANTAGONISM. 

dilate  the  pupil,  to  stimulate  the  heart  and  the  respiration,  to  arrest 
secretion,  to  flush  and  at  the  same  time  dry  the  skin.  Physostigma 
does  not  affect  the  cerebral  functions ;  it  contracts  the  pupil,  para- 
lyzes the  voluntary  muscles,  but  does  not  impair  sensibility,  in- 
creases secretion,  energizes  the  heartbeats  and  raises  the  arterial 
tension,  and  causes  death  by  paralysis  of  the  respiratory  muscles. 
Placed  in  opposition,  we  find  that  the  points  of  difference  are : 
on  the  brain,  atropia  causing  delirious  excitement,  with  hallucina- 
tions and  illusions — physostigma  not  affecting  this  organ  at  all ;  on 
the  pupil,  atropia  causing  dilatation  by  stimulating  the  radiating 
fibers  innervated  by  the  sympathetic — physostigma  causing  con- 
traction by  paralyzing  the  radiating  fibers,  thus  leaving  the  third 
nerve  unopposed ;  on  the  respiration,  atropia  stimulating  the  respira- 
tory center — physostigma  paralyzing  the  muscles  of  respiration  ;  on 
the  heart,  atropia  increasing  the  rate  of  movement  without  adding 
to  the  power — physostigma  increasing  the  power  without  hastening 
the  movements  of  the  heart ;  on  secretion,  atropia  drying  the  mouth 
and  the  secretions  of  the  intestinal  tube — physostigma  increasing 
the  salivary  flow  and  the  secretions  of  the  whole  intestinal  canal ; 
on  the  voluntary  muscular  system,  atropia  causing  paralysis  of  the 
motor  nerves — physostigma  producing  spinal  paralysis.  As  regards 
the  lethal  effects,  the  tendency  to  death  by  paralysis  of  the  respira- 
tory muscles,  produced  by  physostigma,  is  overcome  by  atropia. 
Or,  as  it  is  expressed  by  Professor  Eraser,  "  atropia  prevents  the 
fatal  effect  of  a  lethal  dose  of  physostigma  by  so  influencing  the 
functions  of  certain  structures  as  to  prevent  such  modifications  from 
being  produced  in  them  by  physostigma  as  would  result  in  death. 
The  one  substance  counteracts  the  action  of  the  other,  and  the  re- 
sult is  a  physiological  antagonism  so  remarkable  and  decided  that 
the  fatal  effects,  even  of  three  and  a  half  times  the  minimum  lethal 
dose  of  physostigma,  may  be  prevented  by  atropia." 

The  first  reported  example  of  atropia  poisoning  treated  by  phy- 
sostigma proved  a  success.  The  first  experiment  made  with  the 
definite  purpose  of  ascertaining  whether  an  antagonism  existed, 
also,  apparently  proved  the  point.  But  the  first  sustained  and  suf- 
ficiently extended  experiments  made  to  test  the  antagonism  were 
those  undertaken  by  myself  in  1868,  before  the  published  observa- 
tion of  Bourneville.  While  acknowledging  the  superiority  in  every 
way  of  the  research  undertaken  by  Eraser,  I  respectfully  submit 
that  my  investigations,  as  published  in  my  prize  essay  *  of  the 

*  "  Trans,  of  the  Am.  Med.  Assoc."  for  1869. 


ATKOPIA    AND    PHYSOSTIGMA.  51 

American  Medical  Association,  clearly  preceded  his  by  a  year. 
Claims  of  priority  are,  however,  ungracious,  and  I  do  not  therefore 
urge  mine.  In  his  historical  review,  Professor  Fraser  has  not 
sufficiently,  I  think,  put  my  claim  on  its  proper  basis.  Quoting 
from  my  essay,  he  takes  a  sentence  or  two  from  the  general  conclu- 
sions, which  do  not  adequately  convey  the  whole  meaning  of  my 
researches.  Thus,  he  says:  "Dr.  Bartholow  deduces  a  number  of 
general  conclusions  regarding  the  mutual  counteraction  of  the  two 
substances  on  several  of  the  structures  and  functions  modified  by 
them.  The  following  quotation  contains  an  epitome  of  his  views: 
'Atropia  is  not  a  physiological  antagonist  to  physostigma,  except 
in  regard  to  their  action  on  the  organic  nervous  system.  It  would  be 
improper,  then,  to  use  atropia  against  poisoning  by  Calabar  bean.' J: 
As  I  shall  presently  show,  my  conclusions  have  been  confirmed  by 
subsequent  investigations — the  antagonism  existing  in  the  actions 
on  the  nervous  system  of  organic  life,  as  I  had  demonstrated.  After 
the  detail  of  some  typical  cases,  out  of  a  large  number  of  similar 
experiments,  I  came  to  the  following  conclusions : 

"  Atropia  and  physostigma  are  antagonistic  as  to  their  influence 
over  the  respiratory  movements — atropia  increasing  and  physostig- 
ma retarding  them. 

"  They  are  antagonistic  in  their  action  on  the  heart — atropia 
producing  excitation  of  the  cardiac  ganglia,  and  physostigma  para- 
lyzing them. 

"  They  are  opposed  in  respect  to  their  action  on  the  sympathetic 
• — atropia  causing  increased  action,  and  physostigma  paralyzing  this 
system. 

"  They  have  opposite  effects  on  the  pupil  in  virtue  of  opposite 
effects  on  the  sympathetic — atropia  dilating  the  pupil  by  its  action 
on  the  radiating  fibers  of  the  iris,  and  physostigma  contracting  the 
pupil  by  paralyzing  the  radiating  fibers." 

My  conclusions  of  1868  have  not  been  invalidated  by  the  sub- 
sequent investigations,  and  hence  the  experimental  data  must  have 
been  accurate.  I  therefore  venture  to  submit  that  Professor  Fraser's 
quotation  from  my  essay  does  not  adequately  represent  my  opinions. 
Apparently  without  investigating  on  his  own  account,  and  accept- 
ing a  very  restricted  excerpt  from  my  paper,  Dr.  H.  C.  Wood  * 
says :  "  In  1869,  Professor  Eoberts  Bartholow,  of  Cincinnati,  on  the 
strength  of  a  few  really  indecisive  experiments,  arrived  at  a  conclu- 

*  "  Therapeutics,  Materia  Medica,  and  Toxicology,"  3d  ed.,  p.  320. 


52  PHYSIOLOGICAL   ANTAGONISM. 

sion  opposite  to  that  of  Bourneville."  Dr.  "Wood  has  absolutely  na 
warrant  for  this  positive  assertion.  So  far  from  coming  to  a  con- 
clusion opposed  to  that  of  Bourneville,  it  was  to  the  same  purport, 
and  based  on  a  number  of  really  decisive  experiments.  I  have 
dwelt  on  my  own  views  longer  probably  than  they  deserve,  but  his- 
torical accuracy  is  of  some  moment,  and  no  man  wishes  his  proper 
opinions  mangled  and  distorted  by  others. 

The  quotation  I  have  made  from  Fraser's  paper  indicates  his 
belief  in  the  existence  of  an  antagonism  in  the  lethal  effects  of  atro- 
pia  and  physostigma  of  wide  range,  and  his  experiments,  which  were 
very  numerous  and  carefully  made,  certainly  support  his  opinion. 
The  Committee  of  the  British  Medical  Association  hold  this  antag- 
onism in  less  favor ;  although  they  admit  its  existence,  they  find 
it  is  more  limited  in  range  than  Dr.  Fraser  had  supposed.  Their 
general  conclusion  is :  "  sulphate  of  atropia  antagonizes  to  a  certain 
extent  the  fatal  action  of  Calabar  bean,"  yet  they  maintain  that, 
"  for  all  practical  purposes,  atropia  as  an  antidote  to  Calabar  bean 
is  useless,  and  not  to  be  compared  with  the  effects  of  chloral  hy- 
drate." In  the  first  part  of  this  strong  statement,  the  Committee 
confirm  the  conclusion  to  which  I  had  come,  several  years  before, 
in  respect  to  the  use  of  atropia  as  an  antagonist  to  the  toxic  effects 
of  physostigma. 

The  special  points  of  antagonism  have  been  elaborately  studied 
by  various  observers.  As  respects  the  heart,  atropia  first  causes  a 
rise  of  the  blood  pressure,  but  this  is  followed  by  the  opposite  con- 
dition, or  diminution  of  blood  pressure,  while  the  action  of  the  heart 
continues  accelerated.  Physostigma  slows  the  movement  by  length- 
ening the  diastolic  pause,  and  increases  the  vigor  of  the  contraction, 
and  also  raises  the  arterial  tension.  By  Arnstein  and  Sustschinsky,* 
the  excitability  of  the  cardiac  branches  of  the  vagi  was  found  to  be 
increased  by  physostigma,  and  lessened  by  atropia.  The  experi- 
ments of  Kossbach  and  Frohlich,  in  all  respects  remarkable  and 
novel,t  seem  not  to  confirm  these  observations.  Kohler  J  and  Har- 
nack  and  Wilkowski  §  found  that  physostigma  lessened  the  pulse 
rate,  after  the  peripheral  filaments  of  the  vagi  were  completely 
paralyzed  by  atropia.  HarnackJ  in  a  polemical  paper  strongly 
characterized  by  the  fortiter  in  re,  controverts  the  views  put  forth 

*  "Centralbl.  f.  d.  med.  Wiss.,"  No.  40,  1867. 

f  "Pharmacol.  Untersuchungen,"  Wurzburg,  1873,  p.  77. 

J  "  Archiv.  f.  exper.  Pathol.  u.  PharmacoL,"  i,  p.  277.  §  Ibid.,  v,  p.  402, 

|  Ibid.,  iv,  1876,  p.  146. 


ATKOPIA.   AND    PHYSOSTIGMA.  53 

by  Rossbach  and  Frohlich,  and  by  Rossbach  alone,  in  respect  to 
the  action  of  atropia  on  the  heart  and  on  the  pupil.  Kohler  holds 
that  physostigma  slows  the  heart  by  paralyzing  the  accelerator 
nerve.  It  had  already  been  shown  that  atropia  stimulated  the  ac- 
celerator nerves  (Bezold  and  Bloebaum).  Tachau  *  and  Roeber  f 
maintain  that  the  retardation  of  the  heart  is  due  to  a  paralyzing 
action  of  physostigma  on  the  cardiac  ganglia,  but  Laschkewich^ 
shows  that  this  retardation  is  due  to  stimulation  of  the  inhibitory 
apparatus.  The  rise  of  arterial  tension  produced  by  physostigma  is 
probably  due  to  contraction  of  the  constrictor  fibers  of  the  arteri- 
oles,  since  strong  local  contractions  of  the  intestine  are  produced 
by  this  agent  when  it  is  thrown  into  an  artery  supplying  a  small 
part  of  the  bowel  (Bauer  §).  How  much  soever  the  explanations  dif- 
fer, the  fact  remains  that  atropia  and  physostigma  act  in  an  opposed 
manner  on  the  heart.  As  respects  the  respiration,  there  are  fewer 
differences  of  opinion.  That  physostigma  causes  death  by  paraly- 
sis of  respiration,  the  heart  continuing  in  action  after  respiration 
has  ceased,  seems  abundantly  established.!  On  the  other  hand,  it 
is  generally  conceded  that  atropia  stimulates  the  respiratory  func- 
tion. Physostigma  suspends,  ultimately,  reflex  excitability,  and  is 
a  spinal  paralyzer ;  hence  the  function  of  respiration  is  only  affected 
(Laschkewich,  Tachau).  On  the  other  hand,  the  respiratory  center 
is  stimulated  by  atropia,  and  acceleration  of  breathing  takes  place 
when  the  vagi  have  been  divided  (Bezold  and  Bloebaum).  It  is, 
therefore,  clear  that  these  agents  are  opposed  in  their  actions  on  the 
function  of  respiration. 

The  point  of  opposition  most  conspicuous,  and  that  which  first 
.suggested  the  existence  of  the  antagonism,  is  the  effect  on  the  pupil 
— eserine  causing  contraction,  and  atropia,  dilatation,  of  the  pupil. 
Marked  differences  of  opinion  exist  as  to  the  mechanism  of  the 
antagonism.  By  some,  the  contraction  of  the  pupil  caused  by  eserine 
is  referred  to  a  paralyzing  action  on  the  dilator  fibers  (Fraser,  Hirsch- 
mann  T),  and  by  others  to  a  spasm  of  the  sphincter  fibers  (Griin- 
hagen  and  Rogow,**  Bezold,  and  Goetz).  That  the  latter  view  is 


*  "Archiv.  d.  Heilkunde,"  vi,  69. 

f  Hermann's  "  Lehrbuch  der  experiment.  Toxicologie,"  p.  339. 

J  "  Beobachtungen  iiber  die  physiol.  "Wirkungen  der  Calabarbohne,"  Virchow's  "  Ar- 
chiv," xxxv,  p.  291. 

§  Hermann,  op.  cit.  f  Hermann,  op.  cit.,  p.  341. 

T  "Archiv.  f.  Anat.  u.  Physiol.,"  1863,  p.  309. 

**  "  CentralbL  f.  d.  med.  Wissensch.,"  1863,  p.  677. 


54  PHYSIOLOGICAL   ANTAGONISM. 

correct  seems  supported  by  the  fact  that  the  effect  of  physostigma 
on  the  muscular  layer  of  the  intestine  is  to  induce  tetanic  contrac- 
tion or  spasm.  Further,  when  the  pupil  is  contracted  by  eserine 
the  contraction  is  readily  overcome  by  atropia,  but  the  atropinized 
pupil  resists  the  action  of  eserine. 

The  delirium,  hallucinations,  and  illusions  caused  by  atropia  are 
in  no  respect  affected  by  physostigma.  In  all  of  the  instances  of 
poisoning  by  Calabar  bean  reported,  the  mind  remained  unaffected 
until  near  the  end,  when,  carbonic-acid  poisoning  coming  on,  stupor 
and  drowsiness  supervened.  All  respiratory  poisons,  pure  and  sim- 
ple, are  accompanied  at  the  close  of  life  by  the  carbonic  narcosis 
due  merely  to  the  suspension  of  hsematosis.  Carbonic-acid  narcosis 
is  an  important  element  in  the  morbid  complexus  of  atropia  poison- 
ing. These  agents  do  not,  therefore,  have  an  antagonistic  action  on 
the  cerebrum. 

In  the  spinal  effects  of  atropia  and  physostigma  there  are  obvi- 
ous differences.  They  are  both  paralyzers,  but  atropia  causes,  in 
cold-blooded  animals,  a  subsequent  tetanic  condition.  When  atropia 
and  physostigma  are  administered  simultaneously,  this  tetanic  con- 
dition occurs  at  once — a  fact  which  I  was  the  first  to  demonstrate ; 
and  so  exalted  is  the  reflex  function  of  the  spinal  cord,  that  a  slight 
tap  on  the  surface  of  the  body  causes  a  tetanic  spasm,  the  condition 
in  the  intervals  being  that  of  relaxation.  In  several  of  the  cases  of 
atropia  poisoning,  trismus  was  a  marked  symptom.  Atropia  affects 
the  spinal  cord,  Ringer  and  Murrell  have  shown ;  *  and  the  paraly- 
sis induced  by  it,  they  maintain,  is  largely  spinal,  although  it  does 
impair  the  irritability  of  the  motor-nerve  trunks.  According  to  the 
experiments  of  Dr.  Mary  Putnam  Jacobi,  the  sensibility  of  the  sen- 
sory nerves  is  impaired  by  atropia.  Physostigma,  on  the  other 
hand,  increases  the  irritability  of  the  sensory  nerves,  and  is  a  spinal 
paralyzer,  leaving  the  motor  nerves  and  the  muscles  intact.  These 
agents,  therefore,  agree  on  more  points  than  they  differ  in  their 
action  on  the  spinal  cord. 

As  respects  the  function  of  secretion,  there  is  an  obvious  differ- 
ence in  action  between  physostigma  and  atropia.  An  increased 
flow  of  saliva,  of  the  intestinal  juices,  of  the  tears,  and  of  the  sweat, 
is  a  constant  result  of  the  action  of  physostigma,  and  is  due,  accord- 
ing to  Heidenhain,f  to  a  central  excitation  of  the  secretory  nerves. 
This  conclusion  seems  established  by  the  fact  that  the  increased 

*  "Jour,  of  Anat.  and  Pbysiol.,"  xi,  part  11. 

f  "  Arcb.  f.  d.  gea.  Physiol.,"  v,  p.  40 :  quoted  by  Hermann. 


ATROPIA    AND    PHYSOSTIGMA.  55 

• 

secretion  of  saliva  failed  to  occur  when  the  chorda  tympani  was 
divided  near  the  submaxillary  gland.  The  action  of  atropia  is  the 
opposite  of  this — it  suspends  secretion,  most  probably  by  paralyzing 
the  end  organs  of  the  nerves  in  the  gland,  for,  as  Schiff  has  shown, 
arrest  of  the  secretion  of  the  submaxillary  gland  follows  division 
of  the  chorda  tympani.  Increased  outpouring  of  saliva  takes  place 
when  the  divided  extremity  of  the  nerve  is  galvanized ;  whence 
it  may  be  concluded  that  physostigma  stimulates  the  secretory 
centers. 

On  the  motor  functions,  and  on  the  muscles,  atropia  and  physo- 
stigma act  differently.  I  have  already  emphasized  the  tetanizing 
action  of  atropia  on  cold-blooded  animals,  and  the  trismus  which 
occurs  in  so  many  cases  of  poisoning.  Botkin  *  was  the  first  to 
show  that  atropia  paralyzed  the  motor-nerve  trunks,  and  Laschke- 
wich  f  and  Fraser  proved  that,  in  poisoning  by  Calabar  bean,  the 
irritability  of  the  motor  nerves  and  the  contractility  of  the  muscles 
were  unaffected.  The  action  on  the  motor  functions  is  therefore 
different,  and  not  opposed. 

In  summing  up  the  results  of  the  various  researches,  it  may  be 
regarded  as  established  :  1.  That  physostigma,  or  eserine,  and  atro- 
pia are  antagonistic  in  their  effects  on  the  pupil.  2.  That  they  act 
differently,  but  probably  not  antagonistically,  on  the  heart,  unless 
we  accept  the  views  of  Kohler  and  Bezold  and  Bloebaum — the  for- 
mer maintaining  that  physostigma  paralyzes  the  accelerator  nerves 
of  the  heart,  and  the  latter  that  atropia  stimulates  these  nerves. 
3.  That  they  are  opposed  in  their  action  on  respiration,  physostigma 
paralyzing,  and  atropia  stimulating,  the  respiratory  function.  4. 
That  they  are  not  opposed  in  their  action  on  the  cerebrum,  atropia 
producing  delirium,  and  physostigma  having  no  effect  on  the  cere- 
bral functions,  while  both  cause  more  or  less  carbonic-acid  narcosis. 
5.  That  they  act  differently  and  not  in  an  opposed  manner  on  the 
spinal  cord  and  nerves,  both  producing  paralysis,  but  atropia  does, 
and  physostigma  does  not,  impair  the  irritability  of  motor  nerves. 
As  regards  the  sensory  nerves,  physostigma  augments  their  irri- 
tability, while  atropia  seems  rather  to  lessen  it,  if  any  effect  is 
produced.  6.  That  they  act  oppositely  on  secretion,  physostigma 
stimulating  and  atropia  arresting  the  secretions  in  general. 

It  follows  from  these  conclusions  that  the  lethal  effects  of  phy- 
sostigma, due  to  paralysis  of  respiration,  are  overcome  by  atropia 

*  Virchow's  "  Archiv,''  xxiv,  p.  85.  f  Ibid.,  loc.  cit. 


56  PHYSIOLOGICAL    ANTAGONISM. 

• 

by  sustaining  the  respiratory  function.  The  Committee  of  the 
British  Medical  Association  assert  that  "  the  antagonism  exists 
within  very  narrow  limits,"  but  this  happens  to  be  sufficient  to 
avert  death,  when  doses  little  more  than  lethal  have  been  admin- 
istered ;  still,  the  use  of  physostigma  against  the  lethal  effects  of 
atropia  is  of  doubtful  propriety.  The  paralyzing  effect  of  physo- 
stigma on  respiration  may,  doubtless,  be  successfully  overcome  by 
the  suitable  application  of  atropia. 

ATROPIA  AND   PILOCARPIN. 

The  antagonism  of  action  between  belladonna  and  pilocarpus, 
or  atropia  and  pilocarpin,  is  one  of  the  most  interesting,  as  it  is  one 
of  the  most  exact,  in  the  whole  series  of  antagonisms  of  medicinal 
agents.  The  functional  disturbance  produced  by  atropia  has  been 
sufficiently  elaborated  in  the  preceding  sections.  Our  task  is  now 
chiefly  concerned  with  the  peculiar  powers  and  attributes  of  pilo- 
carpin. The  history  of  jaborandi  affords  us  a  capital  illustration  of 
the  benefit  of  physiological  research  as  applied  to  the  study  of  reme- 
dies. When' it  was  first  introduced,  a  great  many  observers  in  all 
parts  of  the  world  set  about  the  study  of  its  actions.  In  an  almost 
incredibly  short  time  we  were  put  in  possession  of  its  actions,  and 
the  range  of  its  uses  was  at  once  indicated.  All  has  been  abun- 
dantly confirmed  by  trials  on  man,  and  the  first  conclusions  arrived 
at  have  only  been  supported  by  subsequent  investigations.  The 
literature  of  pilocarpus  is  already  vast.  I  will  call  your  attention 
only  to  the  subject  of  its  antagonistic  action.  We  must  first  form 
a  definite  conception  of  what  pilocarpin  does. 

In  a  few  minutes  after  the  alkaloid  pilocarpin  has  been  injected 
subcutaneously,  or  taken  into  the  stomach,  the  action  of  the  heart 
increases,  the  face  flushes,  and  a  subjective  sense  of  heat  is  felt 
throughout  the  body,  but  especially  about  the  face.  The  increased 
action  of  the  heart  does  not  take  place  when  very  large  doses  are 
administered,  and  the  increase  from  small  doses  is  not  maintained 
after  the  characteristic  sweating.  The  pupil  contracts,  spasm  of  the 
accommodation  occurs,  and  recession  of  the  near  point  takes  place. 
More  or  less  headache  is  experienced,  and  there  are  present  a  feel- 
ing of  frontal  tension  and  transient  vertigo.  Soon  after  the  flushing 
of  the  face  and  the  subjective  sense  of  heat  are  experienced,  per- 
spiration begins,  first  on  the  forehead  usually,  and  then  over  the 
whole  body,  and  presently  the  sweating  is  enormous,  the  skin  liter- 
ally pouring  out  water.  Simultaneously  with,  or  often  before,  the 


ATROPIA   AND   PILOCARPIN.  57 

sweating,  the  salivary  glands  become  active,  and  presently  mouthful 
after  mouthful  of  saliva  is  discharged,  so  that  the  quantity  may  be 
measured  by  ounces,  even  pints.  In  some  instances  the  one  secre- 
tion seems  to  be  substituted  for  the  other.  Thus,  when  the  salivary 
flow  is  great,  the  sweat  is  less,  and  vice  versa,  but  the  usual  experi- 
ence is  that  both  secretions  are  enormously  increased.  With  the 
full  development  of  the  salivary  and  sudoral  discharge,  the  pulse 
declines  in  force,  in  volume,  and  in  the  number  of  beats,  the  face 
becomes  pale,  the  strength  diminishes,  and  a  feeling  of  exhaustion 
is  experienced.  The  temperature,  which  was  slightly  or  not  at  all 
increased  during  the  stage  of  excitement,  descends  somewhat  below 
normal  after  the  sweating.  The  secretion  of  urine  is  rather  less 
than  normal,  but  the  bladder  is  irritable  and  the  desire  to  micturate 
is  frequent.  The  surface  of  the  body  is  cool,  and  a  sense  of  chilli- 
ness is  experienced.  Drowsiness  comes  on,  as  a  result  of  the  ex- 
haustion, and  is  not  a  direct  effect  of  the  remedy  on  the  brain. 
When  the  preparations  of  pilocarpus  are  taken  into  the  stomach, 
and,  to  a  much  less  extent,  when  the  active  principle  is  thrown  in 
under  the  skin,  more  or  less  nausea,  even  vomiting,  is  produced, 
and  not  unfrequently  a  watery  diarrhoea. 

The  opposition  of  actions,  between  an  agent  causing  such  func- 
tional disturbances  as  I  have  just  described  and  atropia,  is  apparent 
at  a  glance.  Let  me  briefly  indicate  the  main  points  as  a  prelimi- 
nary to  the  study  of  the  mechanism  of  the  antagonism.  The  first 
increase  in  the  cardiac  movements  caused  by  pilocarpin  is  of  very 
short  duration,  and  is  followed  by  feebleness  of  the  heart  and  dimin- 
ished arterial  tension ;  atropia  induces  and  maintains  a  quickened 
heartbeat  and  a  high  arterial  tension,  during  at  least  the  whole 
duration  of  the  action  of  pilocarpin.  A  subjective  sensation  of  heat 
and  flushing  of  the  face  is  caused  by  both,  but  is  very  transient  in 
the  case  of  pilocarpin.  Contraction  of  the  pupil  is  produced  by 
pilocarpin,  dilatation  by  atropine.  Dryness  of  the  mouth  and  of  the 
skin  results  from  atropia,  profuse  secretion  from  pilocarpin.  Both 
of  these  agents  tend  to  cause  nausea  and  vomiting,  and  a  watery 
diarrhoea.  Both  render  the  bladder  more  or  less  irritable,  and 
atropia  increases  the  urinary  secretion  a  little,  while  pilocarpin 
diminishes  it.  As  regards  the  nervous  system  of  animal  life,  no 
antagonism  exists.  Pilocarpin  does  not  affect  the  cerebral  functions 
directly,  while  atropia  causes  delirium.  Pilocarpin  induces  weak- 
ness of  the  muscular  system,  but  atropia  brings  on  a  tetanic  condi- 
tion by  stimulation  of  the  cord,  and  paralysis  by  an  action  both  on 


58  PHYSIOLOGICAL   ANTAGONISM. 

the  cord  and  on  the  peripheral  motor  nerves.  In  all  those  actions 
involving  the  functions  of  the  organic  nervous  system  there  is  very 
complete  antagonism,  but  in  respect  to  the  nervous  system  of  animal 
life  no  antagonism  is  possible. 

The  only  examples  of  application  of  the  antagonism  to  the 
treatment  of  poisoning,  which  I  have  been  able  to  find,  are  two 
cases  of  poisoning  by  belladonna  liniment,  received  into  University 
College  Hospital  in  charge  of  Dr.  Sydney  Kinger.*  Pilocarpin  was 
injected  subcutaneously  in  both,  without  any  obvious  influence  over 
either.  The  experience  in  the  more  important  of  the  two  cases 
demonstrated  that  one  grain  and  a  third  of  pilocarpin  failed  to  ex- 
cite perspiration,  when  one  third  of  a  grain  of  the  same  sample 
caused  in  healthy  persons  most  profuse  sweating.  It  is  obvious 
that  belladonna  is  relatively  more  intense,  as  it  is  more  prolonged, 
in  its  effects. 

The  first  experiments  to  determine  the  antagonism  of  atropia 
and  pilocarpin  were  those  of  Yulpian,f  and  were  confined  to  the 
salivary  and  sweat  secretions.  "When  the  saliva  and  sweat  are 
pouring  out  in  a  stream  from  the  action  of  pilocarpin,  the  flow  of 
secretion  is  almost  instantly  arrested  by  the  administration  of  atro- 
pia. The  mechanism  of  this  antagonism  has  been  thoroughly  inves- 
tigated by  Yulpian,  £  Langley,  §  Marme,  [  Petrina,^[  and  numerous 
other  investigators.  Pilocarpin  stimulates  the  nerve  ends  in  the 
glands,  and,  as  Heidenhain  long  ago  proved,  atropia  paralyzes  the 
end  organs  of  these  nerves.  The  chorda  tympani  and  the  sympa- 
thetic filaments  distributed  to  the  submaxillary  gland  being  divided, 
pilocarpin  still  has  power  to  cause  increased  secretion,  as  Langley 
has  shown,  thus  proving  that  this  agent  also  stimulates  the  gland 
cells.  In  this  respect,  also,  it  is  probable  that  atropia  has  an  antag- 
onistic action.  The  experiments  of  Langley  on  this  point  have  been 
confirmed  by  Nawrocki,**  Fuchsinger,ff  and  the  other  observers 
just  named. 

The  increase  of  secretion  caused  by  pilocarpin  is  not  limited  to- 
the  skin  and  salivary  glands,  but  extends  to  the  mucous  membrane 
of  the  nose,  bronchi,  and  intestinal  canal,  although  to  a  less  extent. 
The  arrest  of  these  secretions  by  atropia  is  not  less  prompt  and  de- 

*  "  Lancet,"  Mar.  4,  1876.  f  "  Gaz.  Hebdom.,"  1875, 6,  p.  81. 

\  Loc.  tit.  §  "Jour,  of  Anat.  and  Physiol.,"  xi,  part  1,  pp.  173,  et  seq^ 

'     I  Virchow  u.  Hirsch,  "  Jahresbericht,"  1878,  p.  173. 
If  "Deutsch.  Arch.  f.  klin.  Med.,"  xxi,  p.' 258. 
**  "Centralbl.  f.  d.  med.  Wissensch.,"  vi,  p.  97.     ft  Pfliiger's  "Archiv,"  xv,  p.  483. 


ATROPIA   AND    PILOCABPIN.  59 

cided.  The  increased  secretion  caused  by  the  subcutaneous  injec- 
tion of  one  fourth  of  a  grain  of  pilocarpin  muriate,  or  sulphate,  is 
arrested  by  y^¥  grain  of  atropia.  In  a  personal  trial  of  this  quantity 
of  pilocarpin,  I  found  that  the  salivary  flow  began  in  three  minutes, 
and  in  five  minutes  I  was  drenched  by  perspiration,  the  flush  of  the 
face  and  sense  of  warmth  had  ceased,  the  surface  felt  cold,  and  a 
sense  of  extreme  bodily  depression  came  on.  A  marvelous  change 
was  wrought  by  the  subcutaneous  injection  of  -j-J-g-  grain  of  atropia. 
In  three  minutes  the  sense  of  depression  began  to  decline,  in  five 
minutes  the  surface  grew  warm  again,  and  the  flow  of  sweat  and 
saliva  ceased,  so  that  by  the  end  of  ten  minutes  the  disturbances 
caused  by  each  had  disappeared,  and  I  was  in  the  same  condition 
as  if  neither  had  been  taken. 

The  first  effect  of  pilocarpin  on  the  heart  is  to  increase  its  ac- 
tion. This  is  coincident  with  flushing  of  the  face.  Belladonna, 
after  a  very  brief  preliminary  slowing,  greatly  increases  the  action 
of  the  heart,  and  also  flushes  the  face.  The  increased  action  due  to 
pilocarpin  is  brief,  and  is  followed  by  slowing  and  feebleness  of 
movement.  The  resemblance  in  action  is  only  apparent.  The  in- 
creased movement  produced  by  atropia  may  be  explained,  as  we 
have  seen,  in  either  of  two  modes — by  paralysis  of  inhibition,  or  by 
stimulation  of  the  accelerator  fibers.  The  increased  action  due  to 
pilocarpin  is  a  result  of  the  dilatation  of  the  arterioles.  It  is  just 
here  that  the  antagonism  exists.  The  manometric  observations  of 
Kahler  and  Soyka,*  the  experiments  of  Langley,  Hardenhewer,f 
and  Robin,  J  alike  demonstrate  that  pilocarpin  lowers  the  vascular 
tension  by  a  paralyzing  action,  causing  dilatation  of  the  arterioles. 
The  sudden  withdrawal  of  the  blood  to  the  peripheral  vessels  neces- 
sarily causes  increased  action  of  the  heart.  Belladonna  exactly  an- 
tagonizes these  effects:  it  raises  the  arterial  tension  by  inducing 
contraction  of  the  arterioles.  The  depression  in  the  heart's  action, 
and  irregularity  of  rhythm,  due  to  the  action  of  pilocarpin  on  the 
motor  apparatus,  and  which  succeed  to  the  preliminary  increased 
movement,  are  antagonized  by  atropia  (Service).  § 

The  temperature  variations  observed  by  all  who  have  carefully 

*  "  Kymographische  Versuche  iiber  Jaborandi,"  "Arch.  f.  exper.  Pathol.  u.  Pharma- 
col.,"  vii,  p.  435. 

f  "  Berlin,  klin.  Woch.,"  No.  10,  1877. 

\  "  fitude  Physiologique  et  Therapeutique  sur  la  Jaborandi,"  "  Jour,  de  The'rap./* 
various  numbers  for  1875. 

§  "  Jour,  of  Anat.  and  Physiol.,"  April,  1879. 


60  PHYSIOLOGICAL   ANTAGONISM. 

investigated  this  point  are  explained  by  the  circulatory  disturbance. 
According  to  Robin,  jnst  before  sweating  begins,  and  when  it  is 
going  on  actively,  the  temperature  rises,  but  this  does  not  appear  to 
be  a  constant  result.  "When  the  sweating  has  reached  its  maximum 
the  temperature  begins  to  fall,  the  decline  reaching  from  0*5°  to  2° 
F.,  and  this  reduction  of  body  heat  persists  for  several  hours — it 
may  be  for  twenty-four  hours  (Robin,  Curschmann,*  Weber,  f 
Ringer  and  Gould,  ;f  et  al.).  The  decline  of  temperature  caused 
by  pilocarpin  is  antagonized  and  prevented  by  atropia.  By  raising 
the  vascular  tonus,  and  arresting  or  preventing  the  profuse  discharge 
of  saliva  and  sweat,  atropia  restores  the  normal  equilibrium,  and 
•consequently  the  fall  of  temperature  is  prevented. 

Extending  our  investigation  now  to  the  eye,  we  find  that  the 
most  exact  opposition  of  actions  exists  in  the  effects  of  pilocarpin 
and  atropine  on  this  organ.  Myosis,  spasm  of  accommodation,  and 
recession  of  the  near  point  are  produced  by  pilocarpin ;  and  the 
exactly  opposite  effects — dilatation  of  the  pupil,  paralysis  of  the 
accommodation,  and  removal  of  the  distant  point — are  produced  by 
belladonna  (Konigshofer,  Tweedy,  §  Galezowsld,  ||  et  al.). 

That  pilocarpin  directly  affects  the  brain  is  doubtful.  It  is  true, 
headache,  vertigo,  tinnitus  aurium,  etc.,  have  been  observed  from 
considerable  doses;  and  drowsiness,  even  sleep,  accompanies  the 
state  of  languor  and  depression  caused  by  the  profuse  salivary  and 
sudoral  discharge  and  the  lowered  vascular  tonus.  These  secondary 
results  of  the  action  of  pilocarpin  are  not  antagonistic  to  the  de- 
lirium, hallucinations,  and  illusions  of  atropia.  In  the  cases  nar- 
rated by  Dr.  Ringer  the  delirious  excitement  of  belladonna  poison- 
ing was  not  modified  by  the  action  of  pilocarpin — so  that,  viewed 
from  either  the  theoretical  or  the  practical  standpoint,  the  existence 
of  an  antagonism  on  the  brain  muft  be  denied. 

The  nausea  and  vomiting  caused  by  pilocarpin  are  probably  not 
affected,  or  are  increased,  by  atropia.  When  the  action  of  the  drug 
ceases,  the  stomachal  distress  occasioned  by  it  ceases  also — hence,  in 
this  indirect  mode,  atropia  may  prevent  or  arrest  it. 

I  have  already  indicated  some  points  of  similarity  of  action  be- 
tween pilocarpin  and  atropia — the  quickened  heart  and  flushed  face 
• — but  these,  as  has  been  shown,  are  apparent,  and  not  real.  They 

*  "  Berlin,  klin.  Woch.,"  June  18,  1877. 

f  "  Centralbl.  f.  d.  med.  Wissensch.,"  No.  44,  -1877. 

j  "  Lancet,"  Jan.  30,  1875. 

§  Ibid  I  "  Med.  Times  and  Gaz.,"  1877,  ii,  p;  358. 


ATEOPIA   AND    MUSCAKIA.  61 

both  agree,  however,  in  the  insusceptibility  of  children  to  their 
action.  The  observations  of  Ringer  and  Gould  are  very  precise  in 
regard  to  this  insusceptibility  of  children  to  the  action  of  jaborandi. 
They  found  that  the  quantity  which  sufficed  to  produce  profuse 
sweating  in  adults  affected  children  very  slightly  or  not  at  all. 
Children  are  equally  insusceptible  to  the  effects  of  belladonna. 

To  sum  up  the  results  of  the  investigation,  we  find  that  bella- 
donna and  pilocarpus  are  antagonistic  in  their  action  :  1.  On  the 
secretions,  especially  of  sweat  and  saliva,  pilocarpus  promoting, 
and  belladonna  arresting,  them.  2.  On  the  heart  and  arterial  sys- 
tem, pilocarpus  slowing  and  enfeebling  the  heart  and  depressing 
the  vascular  tonus — belladonna  stimulating  the  cardiac  movements 
and  raising  the  arterial  tension.  3.  On  the  eye,  pilocarpus  contract- 
ing the  pupil,  inducing  spasm  of  accommodation,  and  approximating 
the  nearest  and  most  remote  points  of  vision — belladonna  dilating 
the  pupil,  paralyzing  accommodation,  and  making  the  vision  pres- 
byopic. 

On  the  brain  there  is  no  real  antagonism.  The  excitement,  the 
delirium  with  hallucinations  and  illusions,  and  the  subsequent  coma, 
caused  by  atropia,  are  not  affected  by  any  of  the  actions  of  pilo- 
carpin.  The  soporose  state  brought  on  by  the  latter,  as  I  have 
pointed  out,  is  a  secondary  effect,  the  result  of  exhaustion  and  cere- 
bral anaemia. 

Continuing  the  subject  of  the  antagonistic  relations  of  atropia, 
WQ  have  next  to  consider  the  mutual  interactions  of 

ATKOPIA   AND   MUSCARIA. 

As  muscaria,  or  muscarin,  is  comparatively  little  known,  it  may 
be  useful  to  make  a  preliminary  statement  of  its  history  and  char- 
acteristics. It  is  obtained  from  amanita  muscaria — the  fly  fungus. 
We  owe  to  Schmiedeberg  and  Koppe  the  discovery  of  the  alkaloid, 
and  to  Schmiedeberg  and  his  pupils  the  full  and  accurate  informa- 
tion now  in  our  possession  in  regard  to  its  physiological  actions.* 
Muscarin  has  strong  alkaline  and  basic  properties,  uniting  with 
acids  to  form  salts.  It  is  a  colorless  substance  having  the  consist- 
ence of  syrup,  is  readily  soluble  in  water,  and  its  salts  deliquesce 
rapidly  on  exposure  to  air.  It  seems  to  be  actively  toxic — -fa  grain 
producing  in  the  human  subject  very  decided  symptoms.  The 

*  "  Das  Muscarin,  das  giftige  Alkaloid  des  Fliegenpilzes,"  etc.,  Leipzig,  1869 ;  also,,. 
"Arch.  f.  exper.  Pathol.  u.  Pharmacol.,"  iv  and  vi.     Hermann,  op.  cit. 


62  PHYSIOLOGICAL   ANTAGONISM. 

effects,  taking  a  general  view,  are  as  follows  :  Considerable  gastro- 
intestinal disturbance,  nausea,  vomiting,  and  diarrhoea,  and  violent 
colic,  due  to  a  tetanic  contraction  of  the  muscular  layer  of  the  bowel, 
are  produced  by  it.  An  active  and  rather  pleasurable  delirium, 
rambling,  and  incoherence,  not  unlike  that  of  alcohol,  are  caused 
by  the  fungus,  so  that  it  is  used  as  an  intoxicant  by  some  of  the  in- 
habitants of  eastern  Asia.  In  toxic  doses,  the  excitement  is  followed 
by- more  or  less  profound  stupor,  epileptiform  attacks,  trismus,  and 
abolition  of  all  reflex  movements.  During  the  stage  of  pleasurable 
intoxication,  the  pupil  is  contracted,  vision  is  dim,  objects  are  seen 
as  through  a  mist,  and  also,  probably,  double.  The  action  of  the 
heart  is  weakened  and  finally  arrested  in  the  diastole,  the  respiration 
is  labored  and  stertorous,  the  salivary  secretion  is  increased,  the 
surface  of  the  body  becomes  cold,  and  death  ensues  from  failure  of 
the  heart. 

On  the  brain,  it  is  probable  that  muscaria  acts  in  two  modes, 
directly  and  indirectly;  it  first  excites  the  cells  of  the  gray  matter, 
and  ultimately  paralyzes  them  ;  the  heart  being  weakened,  less  blood 
passes  to  the  brain,  and  hence  this  organ  is  in  a  condition  of  anaemia. 
On  the  eye,  muscarin  produces  peculiar  effects.  It  causes  spasm 
of  the  accommodation,  and  a  marked  degree  of  myosis,  by  stimula- 
tion of  the  motor  oculi.  The  vision  is  disturbed,  therefore,  by  the 
spasm  of  the  accommodative  apparatus,  and  by  the  myosis,  which 
limits  the  amount  of  light  admitted  to  the  retina. 

The  secretions  generally  are  increased  by  muscarin,  but  it  espe- 
cially stimulates  the  salivary  secretion.  According  to  Prevost,* 
the  bile  and  the  pancreatic  and  urinary  secretions  are  increased. 
It  promotes  the  salivary  secretion  by  stimulating  the  end  organs  of 
the  nerves,  and  this  is  independent  of  a  centric  influence,  for  it 
takes  place  after  the  trunks  of  the  nerves  have  been  divided.f  It 
is  probable,  if  Prevost's  view  is  correct,  that  the  increase  of  the 
other  secretions  is  due  to  the  same  mode  of  action. 

A  slight  and  momentary  increase  in  the  cardiac  movements  is 
first  produced  by  muscarin,  but  this  is  followed  by  retardation. 
Direct  application  of  this  agent  arrests  the  heart  in  the  diastole, 
but  mechanical,  chemical,  or  electrical  irritation  will  induce  con- 
traction. Section  of  the  vagi  does  not  prevent  this  effect.  It  may 
therefore  be  concluded  that  muscarin  acts  on  the  motor  ganglia  in 

*  "Gaz.  M6d.  de  Paris,"  1870,  iii,  p.  243. 

f  F.  A.  Falck,  "  Der  Antagonismus  d.  Gifte."  Volkmann's  "  Samml.  klin.  Vortr.," 
No.  159,  1879. 


ATEOPIA    AND    MUSCAKIA.  63 

the  substance  of  the  heart,  and  not  on  the  muscle,  nor  on  the  appa- 
ratus of  inhibition.  A  very  considerable  decline  in  the  blood  pres- 
sure is  a  constant  result,  after  a  short  preliminary  rise.  The  walls 
of  the  vessels  relax,  as  Bogosslowsky  *  has  shown,  and,  as  the  ac- 
tion of  the  heart  is  at  the  same  time  depressed,  it  is  obvious  that 
the  vascular  tension  must  be  reduced.  During  the  stage  of  delir- 
ious excitement,  the  respiration  is  rather  hurried,  but  when  the 
subsequent  depression  comes  on,  the  respiration  becomes  slower 
and  shallower,  this  result  being  due  to  a  paralyzing  action  of  mus- 
carin  on  the  respiratory  centers. 

"When  we  come  to  compare  these  disturbances  of  function 
caused  by  muscaria  with  those  produced  by  atropia,  we  must  admit, 
with  Schmiedeberg,  that  no  example  of  physiological  antagonism 
could  be  more  exact.  On  the  brain,  the  intoxication,  with  cerebral 
angemia,  of  muscarin  is  opposed  by  the  active  delirium  and  cere- 
bral hypersemia  of  atropia.  On  the  eye,  the  contracted  pupil  of 
muscaria,  due  to  stimulation  of  the  circular  fibers  innervated  by 
the  third  nerve,  is  opposed  by  the  dilated  pupil  of  atropia,  produced 
by  stimulation  of  the  radiating  fibers,  innervated  by  the  sympa- 
thetic. The  effect  of  atropia  on  the  eye  is  relatively  more  power- 
ful, for,  when  the  pupil  is  contracted  by  muscarin,  it  can  be  dilated 
by  atropine,  but,  when  dilated  by  atropia,  it  can  not  then  be  con- 
tracted by  muscarin.  On  the  function  of  secretion,  the  antag- 
onism is  not  less  striking.  Muscarin  promotes  the  salivary  secre- 
tion by  stimulating  the  end  organs  of  the  nerves  in  the  gland,  and 
atropia  arrests  this  secretion  by  paralyzing  these  nerves.f  But 
atropia  is  relatively  more  powerful  here,  also,  for,  when  the  salivary 
secretion  is  arrested  by  atropia,  muscaria  can  not  reestablish  it,  yet 
the  secretion  caused  by  the  latter  is  promptly  arrested  by  the 
former.  This  opposing  mechanism  probably  extends  to  the  hepatic 
and  pancreatic  secretions  as  well.  The  intestinal  cramp  caused  by 
muscarin  is  removed  by  atropine.  On  the  heart,  nothing  can  be 
more  perfect  than  the  opposing  actions  of  these  agents.  I  brought 
this  fact  forward  in  my  opening  lecture  as  a  striking  exemplifica- 
tion of  the  doctrine  of  antagonism.  If  the  heart  is  arrested  in  the 
diastole  by  muscarin,  it  is  started  again  by  atropia.  If  an  animal 
is  first  brought  under  the  influence  of  atropia,  the  heart  is  not 
stopped  by  muscarin,  notwithstanding  it  is  so  readily  poisoned  by 

*  "  CentralbJ.  f.  d.  med.  Wissensch.,"  97,  1870. 

f  Luchsinger,  u  Die  Wirkungen  von  Muscarin  u.  Atropin  auf  d.  Schweissdriisen  d. 
Katze,"  etc.,  "  Archiv.^f.  d.  ges.  Phys.,"  18,  1878,  p.  501. 


64  PHYSIOLOGICAL   ANTAGONISM. 

this  agent.  The  antagonism  is  equally  exerted  on  the  respiratory 
function — muscarin  lessens  the  respiratory  movements  and  finally 
arrests  them,  while  atropia  stimulates  this  function. 

Thus,  viewed  from  all  sides,  these  agents  are  exactly  antago- 
nistic. Is  a  function  disturbed  by  one  agent  in  a  particular  mode, 
it  is  also  disturbed  by  the  other  agent  in  an  opposite  mode.  In 
fact,  we  should  search  in  vain  for  an  illustration  of  the  law  of 
antagonisms  more  perfect  than  that  subsisting  between  atropia  and 
muscaria. 

Notwithstanding  the  rather  formidable  list  of  antagonisms  in 
which  atropia  appears  on  one  side,  we  have  by  no  means  exhausted 
its  capabilities.  Let  me  invite  your  attention,  briefly,  to  the  sup- 
posed opposition  of  actions  between 

ATROPIA   AND   QUTNIA. 

The  only  systematic  experimental  investigation  of  the  antago- 
nism between  atropia  and  quinia  which  I  have  been  able  to  find  is 
that  of  Pantelejeff.*  Clinical  experience  on  this  point  is  abundant 
enough,  but  we  are  not  now  concerned  with  this  aspect  of  the  ques- 
tion. Pantelejeff  has  ascertained  that  quinia  arrests  the  heart  in 
diastole,  and  that  the  subsequent  administration  of  atropia  causes- 
the  heart  to  resume  its  contractions.  This  result  was  observed  both 
in  frogs  and  in  rabbits.  In  the  latter  animals,  when  the  action  of 
the  heart  was  resumed  after  the  suspension  of  its  movements,  the 
auricles  began  to  contract  before  the  ventricles.  Examination  of 
the  web  of  the  frog's  foot  disclosed  the  interesting  fact  that,  after 
the  subcutaneous  injection  of  quinia,  the  caliber  of  the  arterioles 
was  lessened  by  contraction  of  their  walls,  while  the  opposite  ef- 
fect, or  dilatation,  followed  the  administration  of  atropia.  Quinia 
causes  a  rise  in  the  blood  pressure,  after  a  brief  preliminary  fall, 
and  atropia  retards  it. 

BEOMAL   HYDRATE   AND   ATROPIA. 

One  of  the  subjects  undertaken  by  the  Committee  of  the  British 
Medical  Association,  to  whose  important  labors  I  have  so  often  to 
refer,  was  the  investigation  of  the  antagonism  of  bromal  hydrate 
and  atropia.  This  research  was  especially  in  charge  of  Professor 
McKendrick,  and  the  scope  of  it  was  limited  to  the  lethal  effects. 

*  "  Lancet,"  July  81,  1880,  p.  176. 


ATKOPIA    AND    ACONITE.  65 

All  of  the  facts  are  comprehended  in  the  conclusions  to  which  he 
was  conducted  by  his  experiments,  as  follows: 

"1.  There  is  a  distinct  physiological  antagonism  between  bromal 
hydrate  and  atropia.  2.  After  a  fatal  dose  of  bromal  hydrate,  the 
introduction  of  atropia  arrests  excessive  secretion  from  the  salivary 
glands  and  mucous  surfaces  of  the  lungs,  and  thus  obviates  the  ten- 
dency to  death  from  asphyxia  caused  by  the  accumulation  of  fluids 
in  the  air  passages.  Atropia  also  causes  contraction  of  the  blood- 
vessels, and  thus  antagonizes  the  action  of  bromal  hydrate,  which 
causes  dilatation  of  these  vessels  by  paralysis  of  the  sympathetic 
nerve.  3.  While  atropia  may  save  life  after  a  fatal  dose  of  bromal 
hydrate,  the  converse  apparently  does  not  hold  good,  as  we  never 
have  succeeded  in  saving  life  after  a  fatal  dose  of  atropia  by  the 
subsequent  injection  of  bromal  hydrate." 

ATROPIA   AND   ACONITE. 

The  last  application  of  the  physiological  antagonism  of  atropia 
is  that  with  aconite,  for  which  we  are  indebted  to  Dr.  J.  Milner 
Fothergill.*  These  researches  are  not  extensive,  but  they  probably 
represent  the  actual  state  of  the  antagonism.  A  priori,  a  very  per- 
fect and  extended  opposition  of  actions  would  be  presumed  to  exist. 
Aconite,  a  respiratory  and  cardiac  depressant,  ought  to  be  neutral- 
ized by  atropia,  a  respiratory  and  cardiac  stimulant.  The  facts,  in 
the  main,  support  this  supposition.  "  Thus,  to  a  rabbit  weighing 
2  Ibs.  6  oz.,  I  gave,"  says  Dr.  Fothergill,  "  three  grains  of  atropia, 
and  six  minutes  afterward  -g-J¥  grain  of  aconitine ;  the  animal  sur- 
vived. A  week  afterward,  the  same  rabbit  had  the  aconitine  alone, 
and  died  in  two  hours  and  a  half."  Small  doses  of  atropia,  he 
found,  had  very  striking  effects  on  animals  to  which  lethal  doses  of 
aconitine  had  previously  been  administered.  The  animals  all  re- 
covered from  doses  of  aconitine  which  subsequently  killed  them  all 
when  administered  without  the  atropia.  "  It  was  found,  however, 
that,  if  the  administration  of  the  atropia  was  delayed  beyond  sixteen 
minutes,  it  was  powerless  to  arrest  the  lethal  action  of  aconitine." 

In  the  discussion  of  physiological  antagonisms  thus  far,  atropia 
has  been  one  of  the  agents  concerned  in  every  instance.  But  atro- 
pia also  represents  a  group.  One  of  the  triumphs  of  modern  organ- 
ic chemistry  is  the  reconstruction  of  organic  alkaloids  by  synthesis, 
the  physiological  demonstration  confirming,  in  the  most  unmistaka- 

*  "  The  Antagonism  of  Therapeutic  Agents."    Philadelphia,  1878,  p.  41. 

5 


66  PHYSIOLOGICAL    ANTAGONISM. 

ble  manner,  the  accuracy  of  chemical  methods.  Atropia  has  been 
thus  reconstructed  synthetically  from  two  secondary  products.  Not 
less  interesting  is  the  demonstration  that  apparently  different  alka- 
loidal  principles,  obtained  from  separate  and  independent  sources, 
are  the  same.  Atropia,  daturia,  and  hyoscyamia  are  thus  shown 
to  be  identical  in  chemical  composition.  These,  however,  are  so 
closely  related  in  origin  that  identity  of  composition  is  not  surpris- 
ing. A  new  mydriatic  has  been  recently  discovered,  whose  relation- 
ship to  atropia,  on  the  ph}Tsiological  side,  is  most  intimate — diiboisia, 
the  alkaloid  of  duboisia  myoporoides.  This  new  principle  has  the 
same  power  to  dilate  the  pupil,  to  paralyze  the  accommodation,  to 
produce  a  busy  delirium,  with  hallucinations  and  illusions.  It  has, 
also,  the  same  power  to  increase  the  rate  of  cardiac  movement,  to 
raise  the  arterial  pressure,  and  to  flush  the  surface,  to  produce  the 
same  stimulating  effect  on  the  respiratory  function,  the  same  rise  of 
temperature.  It  has,  also,  the  same  effect  on  secretion,  and  dries 
the  mouth  and  fauces  in  the  same  degree.  Besides  its  more  ready 
influence  on  the  pupil,  the  more  rapid  decline  of  its  effect,  and  its 
less  irritating  action  on  the  conjunctiva,  besides  its  less  deliriant  and 
greater  hypnotic  power,  duboisia  seems  to  have  the  same  physio- 
logical effects  as  atropia.  The  late  researches  of  Laden  burg  seem 
to  prove  that  duboisia  is  identical  with  hyoscyamia.  In  the  whole 
range  of  the  wide  antagonisms  of  atropia,  duboisia  may  take  its 
place,  and  the  facts  true  of  atropia  are  applicable  to  duboisia  and 
also  to  hyoscyamia.  Duboisia  may,  therefore,  be  substituted  for 
atropia  in  the  antagonism  with  morphia,  with  physostigma,  with 
pilocarpin,  with  muscarin,  with  quinia,  with  bromal  hydrate,  and 
with  aconite.  Special  researches  have  been  conducted  with  duboi- 
sia in  respect  to  the  antagonism  with  muscarin,  and  with  pilocarpin. 
It  exhibited  in  these  trials  precisely  the  same  powers  as  atropia,  al- 
though, on  the  whole,  it  acted  somewhat  more  energetically  in  cor- 
responding doses.  Thus,  in  a  short  time  after  its  introduction  to 
professional  notice,  duboisia  is  as  fully  understood,  in  respect  to  its 
powers  and  uses,  as  belladonna  after  centuries,  but  the  one  is  stud- 
ied by  the  modern  physiological  method,  and  the  other,  coming 
down  with  vague  traditions  and  baseless  theories,  is  only  properly 
understood  at  last  when  the  progress  of  physiological  research  en- 
ables new  investigations  to  conduct  to  right  conclusions. 


LECTUKE  IT. 

CHLORAL  AND  STRYCHNIA  ;  CHLORAL  AND  PICROTOXINE  ;  CHLORAL  AND 
ATROPIA;  OPIUM  AND  VERATRUM  VIRIDE;  OPIUM  AND  GELSEMIUM; 
OPIUM  AND  ACONITE  ;  MORPHIA  SUBCUTANEOUSLY  AND  CHLOROFORM 
BY  INHALATION,  ETC. 

THE  discovery  of  chloral  hydrate  and  the  subsequent  announce- 
ment of  strychnia  as  its  physiological  antagonist,  made  by  Lieb- 
reich,*  have  been  followed  by  numerous  researches,  monographs, 
and  clinical  reports,  so  that  the  literature  of  chloral  is  already  enor- 
mous. As  we  are  now  concerned  in  studying  the  antagonisms  of 
chloral,  I  purpose  reviewing  the  work  done  in  this  direction  only. 
Liebreich  demonstrated  that  animals  in  a  deep  stupor  from  chloral 
intoxication,  the  dose  administered  being  lethal,  were  aroused,  and 
death  was  averted,  by  strychnia.  If,  for  example,  two  rabbits  of 
equal  weight — say  three  pounds — receive  -fa  grain  of  strychnia 
sulphate,  a  fatal  dose,  and  to  one  of  them  fifteen  grains  of  chloral 
be  also  given,  the  former  will  die  in  tetanic  convulsions  in  ten 
minutes,  while  the  latter  will  sleep  two  hours  or  more  quietly,  and 
will  wake  up  in  a  normal  state.  Such  a  striking  exhibition  would 
seem  to  be  conclusive,  but  other  observations  are  necessary.  The 
most  important  arid  elaborate  research,  undertaken  to  determine 
the  supposed  antagonism  of  chloral  and  strychnia,  is  that  of  the 
Committee  of  the  British  Medical  Association,  Dr.  J.  Hughes  Ben- 
nett, Chairman.f  The  Committee  first,  rightly,  settled  the  lethal 
dose  of  each  agent ;  they  next  ascertained  the  result  of  the  simul- 
taneous administration  of  chloral  and  strychnia ;  and  then  the  re- 
sult of  the  administration,  at  varying  intervals,  of  one  subsequently 

*  op.  tit. 

f  "Brit.  Med.  Jour.,"  Oct.  3,  1874,  p.  437,  et  seq. 


68  PHYSIOLOGICAL   ANTAGONISM. 

to  the  lethal  dose  of  the  other  agent.  Their  general  conclusions 
are  as  follows :  "  1.  That,  after  a  fatal  dose  of  strychnia,  life  may 
be  saved  by  bringing  the  animal  under  the  influence  of  chloral 
hydrate ;  2.  That  chloral  hydrate  is  more  likely  to  save  life  after 
a  fatal  dose  of  strychnia  than  strychnia  is  to  save  life  after  a  fatal 
dose  of  chloral  hydrate ;  3.  That,  after  a  dose  of  strychnia  produc- 
ing severe  tetanic  convulsions,  these  convulsions  may  be  much  re- 
duced, both  in  force  and  frequency,  by  the  use  of  chloral  hydrate, 
and  consequently  much  suffering  saved ;  4.  That  the  extent  of 
physiological  antagonism  between  the  two  substances  is  so  far  lim- 
ited that  (1)  a  very  large  fatal  dose  of  strychnia  may  kill  before  the 
chloral  has  had  time  to  act;  or  (2)  so  large  must  be  the  dose  of 
chloral  hydrate  to  antagonize  an  excessive  dose  of  strychnia  that 
there  is  danger  of  death  from  the  effects  of  the  chloral  hydrate ;  5. 
Chloral  hydrate  mitigates  the  effects  of  a  fatal  dose  of  strychnia 
by  depressing  the  excess  of  reflex  activity  excited  by  that  substance^ 
while  strychnia  may  mitigate  the  effects  of  a  fatal  dose  of  chloral 
hydrate  by  rousing  the  activity  of  the  spinal  cord  ;  but  it  does  not 
appear  capable  of  removing  the  coma  produced  by  the  action  of 
chloral  hydrate  on  the  brain." 

A  careful  investigation  of  the  supposed  antagonism  of  chloral 
and  strychnia  has  been  undertaken  by  Husemann.*  He  holds 
that  chloral  is  an  antidote  to  strychnia,  prevents  the  spasms,  and 
averts  death,  and  that  it  has  a  corresponding  effect  in  the  case  of 
the  strychnia  bases  sold  under  the  name  of  brucin.  One  of  the 
earliest  attempts  to  ascertain  whether  the  antagonism  existed  was 
that  of  Rajewski,f  who  found  that  chloral  prevented  or  relieved 
the  cramps  caused  by  strychnia,  and  also  to  a  certain  extent  the 
cardiac  depression,  but  that  strychnia  was  not  in  the  same  degree 
an  antagonist  to  chloral.  In  a  memoir  on  the  treatment  of  poison- 
ing by  chloral,  Erlenmeyer  ;£  holds  that,  while  chloral  is  useful  to 
oppose  some  of  the  effects  of  strychnia,  the  converse  does  not  hold 
good,  and  strychnia  is  not  useful  in  chloral  poisoning.  The  influ- 
ence which  Erlenmeyer's  opinion  might  otherwise  have  is  decidedly 
weakened  by  a  statement  made  in  this  connection,  intended  to  illus- 
trate and  enforce  his  views,  that,  while  morphia  is  an  antagonist 
to  atropia  in  poisoning  by  the  latter,  atropia  is  not  an  antagonist  in 

*  "Antagonistische  und  antidotarische  Studien."     "Arch.  f.  exp.  Pathol.  und  Pbar- 
macol.,"  vi,  p.  345. 

f  "  Centralbl.  f.  d.  med.  Wisscnsch.,"  17,  1870,  p.  261. 

\  "  Prakt.  Arzt,"  xiv,  p.  11.     Quoted  in  "  The  Practitioner." 


CHLOKAL   AND    STEYCHNIA.  69 

poisoning  by  morphia.  Arnould,*  who  has  also  investigated  this 
question  experimentally,  regards  the  antagonism  as  more  limited 
in  scope  than  Liebreich  has  maintained.  This  question  has  also 
been  studied  by  Professor  Ore,f  of  Bordeaux,  who  concludes  that 
strychnia  rather  promotes  than  prevents  the  poisonous  action  of 
chloral. 

What  is  the  teaching  of  clinical  experience  ?  I  have  found  re- 
corded seven  cases  of  strychnia  poisoning,  in  which  chloral  was  the 
chief  or  only  means  of  treatment  employed.  An  equal  number  of 
cases  I  find  in  which  chloroform  inhalations  were  practiced  success- 
fully. Although  the  latter  do  not  come  within  the  range  of  the 
present  subject,  yet,  as  the  effects  of  chloral  are  attributed  by  Lieb- 
reich to  the  disengagement  of  chloroform  in  the  blood,  they  may 
:serve  to  illustrate  and  confirm  the  former.  Of  the  seven  cases  of 
strychnia  poisoning,  in  which  chloral  was  the  chief  or  only  agent 
used,  all  proved  successful.  ~No  facts  could  be  stronger.  I  am 
unable  to  find  any  cases  of  chloral  poisoning  in  which  strychnia 
was  properly  and  adequately  used,  as  it  is  in  animals. 

If  we  now  sum  up  the  evidence,  we  can  not  fail  to  be  convinced 
of  the  antagonistic  action  of  chloral  and  strychnia ;  but  chloral  is 
an  antagonist  to  strychnia  poisoning,  rather  than  strychnia  is  an 
antagonist  to  chloral  poisoning.  The  experience  on  rabbits  shows 
that  -^g-  grain  of  strychnia  is  equivalent  to  fifteen  grains  of  chloral. 
In  the  cases  of  poisoning  in  man,  thirty  grains  of  chloral  subcuta- 
neously  was  sufficient  to  allay  the  spasms  and  avert  death  from  four 
grains  of  strychnia.  But  no  absolute  rule  can  be  laid  down,  since 
the  susceptibility  to  the  action  of  these  poisons  varies  greatly  in 
different  individuals.  As  in  the  published  cases  emetics  were  used, 
and  in  many  instances  the  quantity  of  strychnia  was  merely  esti- 
mated, no  positive  conclusions  can  be  drawn  from  them.  Artificial 
respiration  materially  retards  the  action  of  strychnia,  and  warmth, 
as  Brunton  J  has  shown,  exercises  a  remarkable  influence  in  lessen- 
ing the  effect  of  chloral.  Thus  "  Dr.  Brunton  found  that  an  animal 
wrapped  in  cotton- wool  may  recover  perfectly  from  a  dose  of  chloral 
which  is  sufficient  to  kill  it  when  exposed  to  the  cooling  action  of 
the  air,  and  that  recovery  from  the  narcotic  action  .is  much  quicker 
when  the  temperature  is  maintained  in  this  way,  and  still  more 
xapid  when  the  animal  is  placed  in  a  warm  bath,  provided  this  is 

*  "  Presse  Med.  Beige,"  1870,  No.  9,  p.  69.     Quoted  by  Husemann. 
f  "  Bull.  Gen.  de  Therap.,"  Ixxxiii,  p.  403,  et  seq. 
j  "Jour,  of  Anat.  and  Physiol.,"  May,  1874,  No.  14. 


YO  PHYSIOLOGICAL   ANTAGONISM. 

not  excessive."  Heat  would  therefore  seem  to  be  an  antagonist  to 
chloral,  and  for  an  obvious  reason,  for  heat  increases  the  action  of 
the  heart,  and  thus  opposes  the  depression  of  the  heart,  which  is  a 
main  factor  in  the  toxic  effects  of  chloral.  In  the  treatment  of  the 
toxic  effects  of  strychnia  by  chloral,  the  amount  of  the  latter  ad- 
ministered should  be  determined  by  the  symptoms.  Sufficient 
chloral  should  be  given  to  suspend  the  strychnia  spasms,  for  the 
danger  consists  in  the  stoppage  of  respiration  by  tetanic  fixation 
of  the  respiratory  muscles.  The  amount  required  for  this  will, 
doubtless,  vary  within  considerable  limits,  as  I  have  already  inti- 
mated. In  the  case  of  the  Sioux  Indian,  treated  by  Dr.  Turner,* 
the  quantity  of  strychnia  was  not  known,  but  the  return  of  the 
spasms  from  time  to  time  required  repeated  doses  of  chloral,  one 
hundred  and  five  grains  in  all  being  given  within  five  honrs.  When 
strychnia  is  used  against  chloral  poisoning,  the  objects  to  be  accom- 
plished are  different.  By  stimulating  the  cardiac  and  respiratory 
centers  with  strychnia,  the  tendency  to  cardiac  and  respiratory 
failure  is  prevented.  The  quantity  required  will  be  determined 
by  the  effects ;  but  it  is  probably  much  less  than  theory  indicates. 
The  initial  dose  may  be  -fa  grain,  and  each  succeeding  dose  -^T 
grain,  which  may  be  repeated  every  half  hour,  or  more  frequentlyr 
until  an  approximation  to  the  maximum  is  reached. 

We  have  next  to  study  the  physiological  mechanism,  or  to  as- 
certain how  the  opposition  of  actions  occurs.  A  preliminary  state- 
ment of  the  main  facts  in  the  physiological  actions  of  each  will  in- 
dicate the  antagonistic  points.  Chloral,  with  or  without  a  brief 
stage  of  excitement,  induces  a  sopor  closely  related  to  normal 
sleep,  and,  in  lethal  doses,  coma  and  insensibility.  It  therefore  in 
toxic  doses  suspends  the  cerebral  functions.  It  acts  in  the  same 
way  on  the  spinal  cord ;  it  suspends  the  reflex  functions  and  motil- 
ity,  but  sensibility  is  not  destroyed  until  the  cerebral  functions  are 
suspended.  It  does  not  impair  the  contractility  of  muscle  or  the 
irritability  of  the  motor  nerves.  ,The  action  of  the  heart  is  en- 
feebled, the  arterial  tension  is  lowered,  and  a  very  considerable 
reduction  of  temperature  is  caused.  The  respiration  is  slowed,  then 
made  irregular  and  shallow,  and  finally  arrested.  Death  is  caused 
by  paralysis  of  the  heart  or  of  the  respiration,  or  by  .the  simulta- 
neous arrest  of  both  functions.  Strychnia  does  not  affect  the  cere- 
brum, consciousness  being  retained  until  carbonic-acid  narcosis 

*  "  Med.  and  Surg.  Reporter,"  June  15,  1872. 


CHLOEAL   AND    PICKOmXINE.  71 

comes  on.  It  exalts  the  reflex  faculty  of  the  spinal  cord,  and  is  a 
motor  excitant.  It  stimulates  the  respiratory  center  and  the  car- 
diac motor  ganglia,  and  raises  the  arterial  tension. 

Chloral  and  strychnia  can  hardly  be  regarded  as  antagonistic 
in  their  actions  on  the  functions  of  the  brain,  since  chloral  suspends 
them,  and  strychnia  does  not  affect  them  in  any  way.  In  one  re- 
spect they  have  opposed  effects — chloral  producing  cerebral  anaemia 
and  strychnia  rather  increasing  the  intra-cranial  circulation.  On 
the  spinal  cord  the  antagonism  is  very  complete — chloral  suspending 
the  reflex  and  motor  functions  of  the  cord  and  strychnia  exalting 
both.  Strychnia  stimulates  the  respiratory  and  vaso-motor  centers 
in  the  cord,  and  thus  opposes  and  counteracts  the  most  dangerous 
tendency  of  chloral  narcosis.  The  chief  danger  from  strychnia 
— the  tetanic  fixation  of  the  muscles  of  respiration  due  to  the  ex- 
alted reflex  function — is  removed  by  the  action  of  chloral.  This 
antagonism  is  more  certain  and  effective  than  the  opposite  one,  or 
the  stimulation  of  the  chloralized  spinal  cord  by  strychnia;  whence 
it  follows  that  chloral  is  a  more  useful  antagonist  in  strychnia  poi- 
soning than  is  strychnia  in  chloral  poisoning. 

CHLORAL   AND   PICEOTOXINE. 

Professor  Husemann,  in  the  course  of  his  important  researches 
on  the  antagonisms  of  chloral,  finds  that  picrotoxine  must  be  in- 
cluded among  those  agents  (like  strychnia,  the  strychnia  bases 
known  as  brucin  or  brucia,  and  thebaia,  the  tetanizing  alkaloid  con- 
tained in  opium)  which  are  antagonized  more  or  less  completely  by 
chloral.  The  only  published  researches  on  picrotoxine  and  chloral 
of  any  value  are  those  of  Dr.  J.  Crichton  Browne,  of  the  West  Hid- 
ing Lunatic  Asylum.  It  may  be  necessary  to  state  that  picrotox- 
ine is  the  active  principle  of  cocculus  indicus,  is  not  properly  an 
alkaloid,  and  does  not  combine  with  acids  to  form  salts.  As  regards 
its  physiological  actions,  it  has  distinct  deliriant  and  stupefying 
effects  on  the  cerebrum,  and  causes  epileptiform  or  tonic  and  clonic 
convulsions,  followed  by  coma  and  insensibility.  The  reflex  func- 
tions are  suspended  by  it ;  finally,  the  motor  nerves  lose  their  irri- 
tability, and  the  sensory  nerves  are  ecirly  affected,  their  power  to 
transmit  peripheral  impressions  disappearing  in  the  beginning  of  its 
action.  Respiration  and  the  pulse-rate,  at  first,  for  a  brief  period, 
are  increased,  and  the  temperature  also  slightly  rises,  but  this  pre- 
liminary excitement  is  soon  followed  by  depression — by  lowered 
temperature.  After  the  convulsions  especially,  the  pulse  becomes 


72  PHYSIOLOGICAL   ANTAGONISM. 

feeble  and  irregular,  and  the  respirations  shallow  and  arhythmical. 
A  comparison  of  the  physiological  effects  indicates  antagonistic  ac- 
tion on  the  cerebrum  and  spinal  cord,  but  not  on  the  heart  and  cir- 
culation. A  study  of  the  experimental  evidence  leads  to  the  same 
conclusion.  Dr.  Browne,  after  an  elaborate  investigation,  summa- 
rizes his  views  as  follows :  *  "  Chloral  hydrate  is  physiologically 
antagonistic  to  picrotoxine  in  rabbits  and  guinea-pigs,  and  may 
save  life  when  administered  fifteen  to  twenty  minutes  after  a  fatal 
dose  of  the  latter.  There  is  no  antagonism  exerted  between  these 
two  agents  on  cats,  death  being  caused  by  paralysis  of  the  heart, 
a  result  in  which  both  participate." 

No  corresponding  observations  exist  in  cases  of  accidental  poi- 
soning in  man.  Picrotoxine  is  not  used  with  criminal  intent,  and 
its  scarcity  renders  accidental  poisoning  unlikely.  It  is  highly 
probable,  however,  that  the  convulsions  and  cerebral  excitement 
produced  by  picrotoxine  would  be  prevented  or  relieved  by  chloral. 
It  is  doubtful,  however,  whether  the  stupor  and  insensibility  induced 
by  chloral  would  be  relieved  in  the  same  degree  as  by  strychnia. 
The  experiments  of  Dr.  Browne  show  that  picrotoxine  is  to  a  "  very 
limited  extent  antagonistic  to  chloral."  An  examination  into  the 
mechanism  of  the  antagonism  shows  that  it  must  be  confined  to  a 
few  points — to  the  cerebrum  and  to  the  reflex,  motor,  and  sensory 
functions  of  the  spinal  cord,  and  does  not  extend  to  the  heart  and 
to  the  respiratory  organs. 

CHLORAL   AND   ATEOPIA. 

The  antagonism  of  chloral  and  atropia  was,  I  believe,  first  stud- 
ied by  myself,  and  the  results  were  presented  in  a  paper  read  before 
the  Neurological  Society  of  New  York,  in  1875.  It  has  also  been 
the  subject  of  a  special  study  by  Husemann,f  to  a  limited  extent  by 
Fothergill,  and  has  been  discussed  in  a  clinical  lecture  of  Yolk- 
mann's  series  by  Falck.J  Both  of  these  agents  have  been  suffi- 
ciently set  forth  in  the  whole  range  of  their  physiological  powers, 
and  need  not  therefore  be  presented  anew.  On  the  brain  and  spinal 
cord  they  are  antagonistic  to  a  limited  extent.  Atropia  lessens  the 
sleep-producing  power  of  cliloral,  and  therefore  opposes  the  depres- 
sion of  the  respiratory  and  vaso-motor  centers  produced  by  chloral. 

*  "  Brit.  Med.  Jour.,"  1875,  i,  p.  542.  f  Loc.  til.,  p.  443. 

\  Dr.  Ferd.  A.  Falck.     "  Der  Antagonismus  d.   Gifte."     <%  Samml.  klin.  Vortr.,"  von 
B.  Volkmann,  No.  159,  1879. 


CHLOEAL    AND    ATEOPIA.  To 

On  the  spinal  cord  they  act  in  a  different,  and  in  some  respects,  in 
an  opposed  manner.  The  effect  of  atropia  on  the  spinal  cord  and 
nerves  is  complex.  On  the  cord  it  has  a  tetanizing  action,  and  ex- 
alts the  reflex  irritability  ;  on  the  motor  nerves,  a  paralyzing  effect ; 
and  it  lessens  the  irritability  of  the  sensory  nerves.  Chloral  sus- 
pends the  reflex  function  of  the  spinal  cord,  and  causes  a  paralysis 
which  is  purely  spinal,  since  the  irritability  of  the  motor  nerves 
and  the  contractility  of  the  muscles  are  left  intact.  While  chloral 
and  atropia  are  antagonistic  in  their  action  on  the  cord,  they  both 
produce  motor  paralysis.  A  most  obvious  and  important  antago- 
nism exists  between  the  actions  of  these  agents  on  the  circulation 
and  respiration.  This  is  confirmed  by  experimental  trials  on  ani- 
mals and  by  clinical  observation  on  man.  I  have  always  found  it 
to  be  the  case  in  my  experiments  on  animals,  and  Husemann's  ex- 
periments demonstrate  the  same  truth.  Owing  to  the  fact  that,  in 
animals,  the  more  powerful  and  preponderating  action  of  these 
agents  on  the  brain  prevents  the  antagonism  on  the  heart  and  lungs 
exerting  the  salutary  effect  it  has  in  man,  only  rarely  do  the  experi- 
ments succeed  in  averting  death  from  lethal  doses.  Husemann 
narrates  a  striking  case  of  the  accidental  use  of  atropia  in  poisoning 
by  chloral.  A  man  took  from  20  to  24  grammes  (300  to  360  grains) 
of  chloral  hydrate,  was  profoundly  chloralized,  and,  as  his  pupils 
were  minutely  contracted,  it  was  supposed  that  the  narcosis  was 
due  to  morphia.  Acting  on  this  supposition,  an  injection  of  1-J- 
milligramme  (about  ^  grain)  of  atropia  was  practiced.  Neither 
the  pupil  nor  the  respiration  was  affected.  Faradization  with  the 
electric  brush,  mustard  plasters,  cold  douche  to  the  head  and  breast, 
and  other  measures  were  resorted  to  besides ;  but  the  beneficial  in- 
fluence of  the  atropia  is  regarded  by  Husemann  as  hardly  doubtful. 
While  the  good  effects  of  atropia  in  preventing  death  from  chlo- 
ral by  failure  of  the  heart's  action,  or  of  the  respiratory  function, 
are  probably  very  great,  the  converse  is  not  necessarily  true.  Al- 
though there  are  no  experimental  or  clinical  facts,  it  must  be  evi- 
dent that  chloral  can  act  only  as  morphia  does  under  the  same  con- 
ditions, i.  e.,  moderate  the  strain  on  the  cardiac  and  respiratory 
centers  produced  by  the  excitant  action  of  atropia.  This  is  a  less 
important  service  than  that  rendered  by  atropia  in  chloral  narcosis, 
but  is,  nevertheless,  highly  useful.  The  dose  of  atropia  in  chloral 
narcosis  and  the  frequency  with  which  it  is  to  be  repeated  depend 
on  the  effects  produced.  A  small  dose,  repeated  at  short  intervals, 
until  the  characteristic  effects  on  the  pupil,  mouth,  heart  beat,  and 


PHYSIOLOGICAL   ANTAGONISM. 

respiration  are  produced,  and  then  awaiting  the  antagonistic  action, 
is  better  practice  than  the  administration  of  a  large  dose  at  once.. 
The  return  of  reflex  sensibility,  the  improvement  in  the  pulse  and 
respiration,  and  the  dilatation  of  the  pupil  are  the  evidences  that 
the  antagonist  is  producing  good  effects.  When  these  results  are 
obtained,  all  that  the  antagonist  can  effect  is  done,  and  hence  to 
persist  in  the  further  use  of  it,  unless  the  maintenance  of  the  effect 
is  necessary,  is  to  add  atropia  poisoning  to  chloral  narcosis. 

In  his  research  on  a  supposed  antagonism  between  thebaia  and 
chloral,  Husemann  found  that  this  antagonism  existed  to  a  limited 
extent.  Chloral,  however,  only  intensifies  the  effects  of  morphia 
and  codeia.  In  a  number  of  experiments  on  this  point,  I  have 
found  that  morphia  and  chloral  are  synergists,  or  promote  each, 
other's  activity,  and  that  they  can  be  more  safely  administered  by 
combination  with  atropia,  which  counteracts  the  cardiac  and  re- 
spiratory depression  caused  by  them,  and  which  constitutes  the 
great  danger  in  their  use  in  man,  as  in  the  inferior  animals. 

THE   ANTAGONISTS   TO   THE   CARDIAC    AND   RESPIRATORY   DEPRESSANTS. 

We  have  now  reached  a  very  interesting  and  important  depart- 
ment of  our  subject.  From  the  physiological  and  clinical  point  of 
view  alike,  it  is  most  useful  to  know  the  mutual  interactions  and 
reciprocal  relations  of  those  remedies  which  act  on  the  lungs  and 
heart.  It  is  by  the  extension  of  our  knowledge  in  this  direction 
that  we  may  hope  by  various  combinations  to  improve  the  curative 
powers  and  enhance  the  safety  of  administration  of  these  important 
remedies. 

Let  us  first  consider  opium  and  veratrum  viride.  It  has  long 
been  known  to  practical  physicians  in  this  country  that  the  tincture 
of  opium  counteracts  the  depression  of  the  circulation  caused  by 
veratrum  viride.  I  can  not  trace  this  fact  to  its  original  source. 
The  first  example  of  opium  poisoning  treated  by  veratrum  viride  I 
have  been  able  to  find,  is  that  of  Dr.  J.  S.  Todd,*  of  Georgia.  A 
man  took  with  suicidal  intent  an  amount  of  laudanum  equivalent 
to  forty  grains  of  crude  opium.  The  treatment  of  the  opium  nar- 
cosis consisted  in  the  administration  of  emetics,  which  did  not  act, 
however,  until  long  after  complete  absorption  ;  the  subcutaneous 
injection  of  atropia  until  the  pupils  were  fully  dilated  ;  and  the  sub- 
cutaneous injection  of  whisky  and  tincture  of  veratrum  viride.  Six. 

*  "Am.  Jour,  of  the  Med.  Sci.,"  Jan.,  1873,  p.  131. 


OPIUM   AND    VERATBUM    VIEIDE.  5 

drops  of  tincture  of  veratrum  viride  were  administered,  in  all,  hy- 
podermically.  So  many  agents  being  jointly  used,  it  is  difficult  to 
assign  to  each  its  exact  share  in  the  result.  Dr.  Todd  holds  that 
the  atropia  did  no  good,  and  to  the  veratrum  viride  he  mainly  at- 
tributes the  recovery.  Dr.  Haldeman,*  of  Zanesville,  Ohio,  reports 
successful  cases  of  the  treatment  of  opium  narcosis  by  veratrum 
viride.  There  has  been  no  published  experimental  evidence  sub- 
mitted in  support  or  disapproval  of  the  popular  professional  opinion 
in  regard  to  this  antagonism.  During  the  past  summer  and  fall  I 
made  a  number  of  observations,  on  rabbits  chiefly,  at  my  laboratory 
in  Jefferson  College.  I  ascertained  first  that  the  minimum  lethal 
dose  of  fluid  extract  of  veratrum  viride  (U.  S.  P.)  was  three  minima 
to  the  pound  weight.  This  produces  nausea,  some  diarrhoea,  weak 
pulse,  labored  respiration,  and  convulsions,  death  occurring  from 
suspension  of  breathing.  To  this  quantity  of  veratrum  viride  three 
to  five  minims  (according  to  the  weight  of  the  animal)  of  Ma- 
gendie's  solution  of  morphia  (gr.  xvi-Jj)  seems  to  be  antagonistic. 
When  used  in  the  proper  proportion,  the  nausea  and  vomiting,  the 
muscular  paresis,  the  paralysis  of  the  respiratory  muscles  and  the 
labored  breathing,  the  feeble  action  of  the  heart,  were  all  prevented, 
and  the  life  of  the  animal  was  preserved.  When  the  effects  of  the 
morphia  preponderate,  the  pupil  becomes  minutely  contracted, 
drowsiness  deepening  into  stupor,  and  morphia  convulsions  come 
on,  but  the  effects  produced  by  veratrum  viride  disappear.  Cor- 
responding observations  were  made  on  frogs.  The  antagonism 
between  opium  and  veratrum  viride  is  clearly  established,  but  the 
distance  apart  at  which  their  effects  are  exerted  has  not  been  defi- 
nitely ascertained — most  of  the  experiments  being  performed  by 
the  simultaneous  administration  of  the  two  agents.  I  found,  how- 
ever, that  the  antagonism  was  exerted  after  ten  and  twenty  min- 
utes, but  further  experiments  must  be  made,  to  learn  if  it  is  suffi- 
cient at  a  longer  interval.  It  is  further  ascertained  that,  whether 
opium  be  used  against  veratrum  viride,  or  veratrum  viride  against 
opium,  the  antagonistic  action  is  equally  displayed.  The  cases  nar- 
rated by  Dr.  Todd,  of  Georgia,  and  Dr.  Haldeman,  of  Ohio,  are 
apparently  conclusive  as  to  the  existence  of  the  antagonism  in  man. 
We  are  next  concerned  to  ascertain  its  nature  or  mechanism, 
Is  there  an  explanation  afforded  us  in  the  physiological  actions  of 
the  two  agents?  Veratrum  viride  does  not  affect  the  mental  func^ 

*  "  Cincinnati  Lancet  and  Clinic,"  1879,  and  1880,  p.  465. 


6  PHYSIOLOGICAL    ANTAGONISM. 

tions,  but  causes  cerebral  anaemia ;  opium  produces  excitement  of 
the  mental  functions,  quickly  followed  by  stupor,  coma,  and  in- 
;  sensibility.  Yeratrum  viride  depresses  the  vaso-motor  functions, 
lessens  the  arterial  tension,  and  lowers  the  temperature  of  the 
body ;  opium  in  doses  less  than  lethal,  especially  in  the  form  of 
morphia  used  subcutaneously,  stimulates  the  vaso-motor  functions, 
raises  the  tension  of  the  arterial  system,  and  does  not  reduce,  but 
maintains,  the  temperature.  On  the  heart  muscle  veratrum  viride 
acts  as  a  direct  depressant,  and  on  the  respiratory  muscles  as  a  par- 
alyzer;  opium  in  doses  less  than  lethal  has  a  great  power  to  main- 
.tain  the  heart  and  respiration.  Yeratrum  viride  increases  secretion 
generally,  the  saliva  and  sweat  especially;  opium  diminishes  secre- 
tion usually,  but  under  some  circumstances  increases  perspiration. 
Yeratrum  viride  is  a  paralyzer  by  depressing  the  motor  spinal  func- 
tions, the  motor-nerve  trunks  and  the  muscles  remaining  intact ; 
opium  in  less  than  lethal  doses  opposes  rather  than  promotes  the 
paralyzing  effects  of  veratrum. 

I  can  not  too  strongly  insist  on  the  difference  in  the  action  of 
medicinal  and  lethal  doses  of  opium.  In  employing  opium  against 
the  toxic  effects  of  veratrum  viride,  no  good  can  result  from  the 
administration  of  such  doses  as  will  rather  approximate  the  effects 
of  opium  to  those  of  veratrum  viride.  It  should  be  kept  in  mind 
that  it  is  the  stimulating  effect  of  opium  which  renders  it  an  antag- 
onist to  veratrum  viride.  ~No  absolute  rule  as  to  quantity  can  be 
prescribed  with  certainty.  Referring  to  the  clinical  experience  now 
available,  we  obtain  practical  data  to  serve  for  a  decision  of  the 
question.  In  the  case  of  an  infant  three  weeks  old,  poisoned  by 
four  or  five  drops  of  laudanum,  two  and  three  fourths  drops  of  tinc- 
ture of  veratrum  viride  dispelled  the  narcosis.  An  adult  female, 
aged  thirty,  took  a  quantity  of  laudanum,  supposed  to  be  about  two 
ounces,  and  was  in  a  condition  of  profound  narcosis,  respirations 
only  3J-  a  minute,  when  six  drops  of  veratrum  viride  tincture  were 
injected  subcutaneously.  In  a  half  hour  she  could  be  roused,  but 
lapsed  back  immediately  into  a  comatose  state,  and,  as  she  could 
then  be  induced  to  swallow,  three  drops  of  the  tincture  were  given 
-every  two  or  three  hours  by  the  stomach  until  she  recovered  en- 
tirely, which  occurred  in  a  few  hours.  The  whole  amount  of  the 
veratrum  viride  administered  did  not  exceed  fifteen  drops  of  the 
-tincture.  In  a  case  reported  by  Dr.  Sholl,  of  Alabama,  a  negro 
boy  took  an  overdose  of  morphia,  prescribed  for  the  hiccough  of 
typhoid  fever,  the  quantity  not  stated.  The  usual  narcosis  followed, 


OPIUM    AND    GELSEMIUM. 

and  eighteen  drops  of  Norwood's  tincture  of  veratrum  viride  were 
administered,  with  the  remarkable  effect  that  in  one  hour  the  symp- 
toms of  poisoning  had  disappeared.  Dr.  A.  Sheller  also  reports  a 
case  in  which  profound  narcosis,  produced  by  the  administration 
of  If  grain  of  morphia  within  eight  hours,  was  relieved  entirely 
within  a  few  hours  by  the  use  of  thirty  drops  of  Tilden's  fluid  ex- 
tract of  veratrum  viride.*  Unfortunately  the  details  in  these  cases 
are  not  exact,  but  one  patient  certainly  received  a  lethal  quantity, 
and  the  others  may  or  may  not  have  recovered  without  assistance. 
Notwithstanding  these  defects  in  the  details  of  the  reported  cases, 
the  proof  of  the  utility  of  the  veratrum  viride  seems  conclusive. 
Clinical  experience  is  thus  in  accord  with  the  results  of  experiment. 
If  further  investigations  confirm  them,  the  antagonism  of  opium 
and  veratrum  viride  will  take  high  rank  for  the  efficiency  and  ex- 
tent of  its  range. 

Opium  and  Gelsemium. — The  actions  of  gelsemium  are  similar 
to  those  of  veratrum  viride,  but  they  differ  also  in  important  par- 
ticulars. Gelsemium  is  more  distinctly  a  paralyzer.  It  causes 
dropping  of  the  upper  eyelid,  dilatation  of  the  pupil,  and  diplo- 
pia,  by  paralyzing  the  third  nerve.  The  cerebral  effects  are  ver- 
tigo, drowsiness,  and  stupor;  but  no  disturbance  of  intellect  results 
from  it,  a]though  a  comatose  state  is  brought  on  by  carbonic-acid 
narcosis.  Gelsemium  paralyzes  respiration,  this  function  ceasing 
before  the  heart's.  It  is  not  an  arterial  sedative,  as  usually  sup- 
posed, the  depressed  circulation  being  secondary  to  the  respiratory 
depression.  The  paralyzing  action  of  gelsemium  is  spinal,  since 
neither  the  motor  nerves  nor  the  muscles  are  affected.  It  is  obvious 
that  opium,  in  ordinary  medicinal  doses,  antagonizes  the  actions  of 
gelsemium,  prevents  the  respiratory  and  cardiac  depression,  and 
averts  death,  unless  the  nervous  centers  are  entirely  overwhelmed 
by  the  amount  of  the  poison.  In  a  case  of  poisoning  by  gelsemium 
narrated  by  Dr.  George  S.  Court wright.f  we  have  a  striking  example 
of  the  curative  effect  of  the  antagonist.  A  physician  took  by  mis- 
take, in  the  dark,  what  he  supposed  was  a  teaspoonfnl  or  two  of  the 
tincture  of  cinchona,  but  proved  to  be  the  tincture  of  gelsemium., 
In  half  an  hour  he  began  to  experience  the  paralyzing  effect?,  had 
the  drooping  eyelids,  the  dilated  pupil,  the  hanging  jaw,  the  labored 
respiration,  and  the  weak  pulse  produced  by  gelsemium.  The  phy- 
sician called  in,  Dr.  Courtwright,  recognizing  the  similarity  of  thia 

*  Haldeman,  "  Cincinnati  Lancet  and  Clinic,"  Aug.,  1879. 
f  "  Cincinnati  Lancet  and  Observer,"  xxxvii,  1876,  p.  961. 


78  PHYSIOLOGICAL    ANTAGONISM. 

to  belladonna  poisoning,  at  once  injected  morphia  subcutaneously. 
The  quantity  used  was  estimated  at  one  half  to  three  fourths  of  a 
grain,  and  this  was  repeated  in  three  minutes,  at  the  end  of  seven 
minutes,  and  again  at  the  end  of  eleven  minutes,  making  four  in- 
jections, or  two  grains  of  morphia,  hypodermically.  Besides  this, 
he  was  given  half  a  grain  of  morphia  when  able  to  swallow.  After 
the  third  injection,  "  he  partially  raised  his  arm,  and  with  an  eifort, 
-and  by  an  assistant  holding  up  the  lower  jaw,  he  said,  £Be  spry.' ' 
In  two  hours  the  paralysis  ended,  and  the  Doctor  was  able  to  give 
an  account  of  the  accident.  It  is  hardly  doubtful  that  a  tablespoon- 
ful  of  the  tincture  of  gelsemium  had  been  taken,  for  a  less  quantity 
•could  not  produce  such  severe  symptoms.  The  amount  of  morphia 
used  in  antagonism  seems  rather  excessive,  but,  as  it  was  estimated, 
it  is  probable  the  amount  actually  administered  was  less  than  sup- 
posed. The  very  remarkable  improvement  which  followed  the  in- 
jection of  morphia  is  a  striking  evidence  of  the  completeness  and 
fidelity  of  the  antagonism  on  man. 

I  have  pursued  the  same  line  of  research  with  morphia  and  gel- 
semium as  with  morphia  and  veratrum  viride.  On  rabbits,  the 
lethal  dose  of  the  fluid  extract  of  gelsemium  (U.  S.  P.)  is  about  five 
minims  to  the  pound  weight.  The  antagonism  is  admirably  shown 
on  the  pupil,  on  the  respiration,  and  on  the  action  of  the  heart,  but 
I  have  not  been  able  to  avert  death  from  the  cerebral  effects  of  both. 
The  entire  disappearance  of  the  symptoms  due  to  gelsemium  is  first 
seen,  but  then  come  on  the  cerebral  effects  of  morphia,  and  convul- 
sions usually  terminate  life.  In  man,  as  we  have  seen,  owing  to 
the  extent  and  complexity  of  the  cerebral  structures,  the  effects  of 
morphia  are  diffused  into  the  higher  centers,  and  therefore  not  ex- 
pended on  the  lower  centers  alone. 

Morphia  in  the  same  way  antagonizes  the  depressing  effect  of 
aconite  on  the  respiration  and  on  the  heart.  Although  in  the  in- 
ferior animals,  as  is  the  case  with  the  other  members  of  the  same 
group,  the  lethal  effects  of  both  agents  ara  exerted,  the  antagonism 
is  conspicuously  exhibited  in  the  support  of  the  heart  and  the  main- 
tenance of  respiration.  Clinically,  the  same  facts  have  been  repeat- 
edly observed,  and,  incases  of  accidental  use  of  aconite  in  poisonous 
quantity,  death  has  been  averted  by  the  timely  administration  of 
opium  or  morphia.  As  the  facts  already  set  forth  in  regard  to  the 
opposed  actions  of  opium  and  veratrum  viride  are  equally  applica- 
ble to  opium  and  aconite,  further  discussion  of  the  latter  may,  there- 
fore, be  unnecessary. 


MORPHIA    AND    CHLOROFORM.  79 

Morphia  and  Cocaine,  Theine,  Caffeine,  and  Guaranine. — One 
of  the  most  interesting,  if  not  one  of  the  most  important,  of  the  re- 
searches undertaken  by  the  Committee  of  the  British  Medical  As- 
sociation is  that  series  to  determine  a  supposed  antagonism  between 
morphia,  on  the  one  hand,  and  the  alkaloids  of  tea,  coffee,  coca,  and 
guarana,  on  the  other.  It  was  found  that  the  physiological  action 
of  these  alkaloids  was  practically  identical.  They  produce  "  cere- 
bral excitement,  succeeded  by  coma,  when  the  quantity  is  large ; 
loss  of  sensibility,  which  is  partial  when  the  dose  is  small,  complete 
when  the  dose  is  large;  tetanic  spasms  and  convulsions;  paralysis 
of  the  posterior  columns  of  the  spinal  cord  and  the  peripheral  sen- 
sory nerves,  leaving  the  anterior  columns  and  the  peripheral  motor 
nerves  unaffected ;  at  first  increase  and  finally  diminish  the  force 
&nd  frequency  of  the  cardiac  contractions,  and  first  irritate  and  then 
paralyze  the  vaso-motor  nerves."  It  is  obvious  that  morphia  antago- 
nizes some  of  these  actions,  and  promotes  others.  Empirically, 
strong  decoctions  of  tea  and  coffee  are  employed  in  opium  poison- 
ing, because  it  is  a  matter  of  common  experience  that  these  infu- 
sions cause  wakefulness.  Cases  of  opium  narcosis,  produced  by  a 
quantity  barely  sufficient  to  induce  lethal  effects,  have  been  relieved 
by  these  means  alone,  but  usually  other  measures  of  greater  activity 
are  employed.  The  researches  of  the  committee  demonstrate  that 
there  is  some  foundation  for  this  popular  opinion.  They  find  that 
theine  is  antagonistic  to  meconate  of  morphia,  and  that  the  action 
of  one  so  far  modifies  that  of  the  other  as  to  save  life  after  a  fatal 
dose  of  either. 

Morphia  and  Chloroform. — As  paralysis  of  the  heart  or  of  the 
respiration,  or,  it  may  be,  the  simultaneous  depression  of  both  func- 
tions, is  the  mode  of  dying  by  chloroform  and  by  other  anaesthetics 
used  for  the  same  purpose,  it  is  extremely  desirable  to  possess  an 
agent  which  will  antagonize  and  prevent  this  fatal  tendency.  I  do 
not,  I  believe,  exaggerate  the  fact,  when  I  state  that  we  possess 
such  an  agent  in  the  subcutaneous  injection  of  morphia.  It  is  an 
extraordinary  circumstance  that  surgeons  have  been  so  indifferent 
to  the  remarkable  results  obtained  by  the  employment  of  mixed 
anaesthesia.  Claude  Bernard,  and,  about  the  same  time,  E"ussbaum, 
the  one  in  his  laboratory,  the  other  in  the  clinical  theatre,  demon- 
strated the  great  utility  of  the  ansesthesia  procured  by  the  injection 
of  morphia  and  the  inhalation  of  chloroform— "  mixed  anaesthesia." 
Although  the  methods  of  Bernard  *  and  of  Nussbaum  are  usually 

*  "Bull.  C&i.  de  Therap.,"  Ixxvr,  p.  241. 


80  PHYSIOLOGICAL   ANTAGONISM. 

supposed  to  be  the  same,  they  differ — Bernard  administering  the 
morphia  a  few  minutes  before  beginning  the  inhalation,  and  Nuss- 
baum  giving  it  after  the  inhalation  is  well  under  way.  In  this 
country,  the  method  of  "  mixed  anaesthesia"  was  advocated  some 
years  ago  by  Professor  William  Warren  Greene.  Last  year  the 
subject  was  again  brought  forward  in  an  admirable  memoir,  by  Dr. 
J.  C.  Reeve,*  of  Dayton,  Ohio.  In  France,  interest  in  the  subject 
has  lately  greatly  revived,  and  several  theses  have  appeared — the 
most  important  being  that  of  Dr.  S.  Bossis.f  In  my  "Manual 
of  Hypodermic  Medication,"  the  first  edition  of  which  appeared 
in  1867,  I  called  attention  to  this  important  subject,  citing  the  ob- 
servations of  Bernard  and  Nussbaum. 

Morphia  and  chloroform  act  on  the  same  cellular  elements  of 
the  brain,  and  agree  in  the  production  of  anaesthesia,  but  they  are 
opposed  in  their  action  on  other  structures  and  organs — an  opposi- 
tion which  renders  their  combined  use  safer.  When  morphia  is  in- 
jected subcutaneously  before  the  inhalation  of  the  anaesthetic  has 
begun,  the  irritability  of  the  bronchial  mucous  membrane  is  so  far 
diminished  as  to  permit  the  inhalation  to  proceed  quietly ;  the  stage 
of  excitement  is  prevented,  and  consequently  the  danger  of  the  as- 
phyxia which  occurs  under  these  circumstances;  the  nausea  and 
vomiting,  which  interfere  with  the  progress  of  the  inhalation  and 
which  may  indirectly  produce  serious  consequences,  are  also  obvi- 
ated ;  and  the  stage  of  narcosis  is  prolonged  without  the  need  of  fur- 
ther inhalation.  The  after-pain,  the  nausea  and  vomiting,  and  the 
systemic  depression  which  result  from  the  inhalation  of  the  anaes- 
thetic, and  the  sometimes  dangerous  syncope,  are  also  in  a  large 
measure  prevented.  By  a  careful  adaptation  of  the  relative  pro- 
portions of  chloroform  and  morphia,  a  state  of  insensibility  to  pain 
without  loss  of  consciousness  is  induced.  In  the  words  of  Bossis — 
"There  may  be  obtained  in  man,  with  a  little  attention,  by  the 
combined  action  of  chloroform  and  morphia,  a  state  of  complete  in- 
sensibility to  pain,  with  preservation  to  a  partial  extent  of  the  in- 
telligence, of  the  tactile,  auditory,  and  visual  sensibility,  and  of  the 
voluntary  movements.  From  the  practical  point  of  view,  the  anal- 
gesia obtained  by  the  combined  action  differs  completely  from  the 
demi-anaesthesia  caused  by  the  employment  of  chloroform  or  ether 
singly,  in  that  it  is  not  preceded  or  accompanied  by  a  period  of 


*  "  Trans,  of  the  Ohio  State  Med.  Soc.,"  for  1879. 

f  uEssai  sur  1' Analgesic  Chirurgicale,"  etc.,  Paris,  1879. 


STKYOHNIA   AND    ANTAGONISTS.  81 

hyperaesthesia  with  violent  excitement,  and  the  tendency  to  exag- 
gerated reflex  arrests  of  the  heart  and  after  syncope." 

Clinical  experience  with  the  "  mixed  method  "  seems  to  support 
the  deductions  of  experiment  in  regard  to  the  antagonistic  action  of 
morphia  to  the  cardiac  and  respiratory  failure  induced  by  the  anaes- 
thetics. A  large  experience  is  necessary  to  settle  the  question,  how- 
ever, and  the  failures  which  may  result  from  pathological  conditions 
of  the  organs  concerned  must  be  eliminated.  There  can  be  no 
doubt,  however,  from  the  experience  thus  far  accumulated,  that 
morphia,  by  the  method  of  Bernard,  greatly  facilitates  the  induction 
of  anaesthesia  and  lessens  its  dangers.  I  have  maintained  that  for 
this  purpose  the  combination  of  morphia  and  atropia  should  be  pre- 
ferred to  morphia  alone,  because  of  the  power  of  atropia  to  stimulate 
both  heart  and  lungs.  It  might  be  supposed,  on  superficial  reflec- 
tion, that  atropia  would  be  better  than  morphia,  but  it  should  be 
remembered  that  stimulation  has  its  inevitable  reaction.  Morphia 
has  a  power  of  support  not  possessed  by  atropia.  "When  adminis- 
tered together  under  the  circumstances,  the  evil  effects  of  both  are 
antagonized,  and  the  power  of  both  to  support  the  heart  and  respi- 
ration is  utilized.  The  quantity  of  morphia  should  rarely  exceed 
one  fourth  of  a  grain,  and  that  of  atropia,  one  one-hundredth  of  a 
grain.  The  method  of  Bernard  should  be  preferred  to  that  of  Nuss- 
baum,  because  it  facilitates  the  inhalation,  and  not  less  secures  the 
advantages  of  the  "  mixed  method." 

Strychnia  as  a  Stimulant  of  the  Respiratory  Function. — The 
importance  of  atropia  as  a  special  stimulant  of  the  respiratory  func- 
tion has  been  frequently  alluded  to.  The  resemblance  in  the  spinal 
actions  of  atropia  and  of  strychnia  has  been  manifest  in  the  study 
of  these  agents.  Atropia,  in  therapeutical  works,  is  sometimes, sug- 
gested as  an  opponent  and  antagonist  of  strychnia ;  it  is  so  placed 
in  Gubler's  "  Commentary  on  the  French  Codex."  Hardly  any 
statement  could  be  more  fallacious.  In  some  experimental  investi- 
gations made  some  years  ago,  I  found  that  atropia  intensified  the 
effects  of  strychnia,  and  hastened  death  by  contributing  to  the  te- 
tanic fixation  of  the  muscles  of  respiration.  We  find  that  strychnia 
stands  next  to  atropia  as  a  stimulant  to  the  respiratory  function. 
Through  the  heightened  reflex  activity  of  the  spinal  cord  and  of  the 
respiratory  centers  in  the  medulla,  strychnia  causes  death  by  spasm 
of  the  respiratory  muscles  and  asphyxia.  It  mast  therefore  antago- 
nize those  agents  which,  like  aconite,  cause  death  by  paralysis  of 
the  respiratory  muscles.  This  supposition  is  confirmed  by  experi- 
6 


82  PHYSIOLOGICAL    ANTAGONISM. 

ment.  In  an  interesting  series  of  experiments  to  test  this  antago- 
nism, Dr.  Fothergill  found  that  a  lethal  dose  of  aconitine  was  en- 
tirely overcome  by  a  quantity  of  strychnia  twice  as  great  as  the 
lethal.  The  animals  given  the  aconitine  alone  died ;  the  same  ani- 
mals receiving  the  aconitine  with  the  strychnia,  in  previous  experi- 
ments, recovered.  The  existence  of  the  antagonism  is  therefore 
undoubted. 

An  opposition  of  actions  has  been  determined  to  exist  between 
strychnia* and  nitrite  of  amyl.  These  substances  act  in  an  opposite 
manner  on  the  nervous  system  of  animal  life  and  on  the  sympathetic 
system.  Amyl  nitrite  suspends  the  reflex  function  of  the  spinal  cord 
and  causes  paralysis  of  the  muscular  system,  and  death  ensues  from 
paralysis  of  the  respiratory  muscles.  The  most  characteristic  effects 
are  those  on  the  heart  and  the  arterial  system.  It  depresses  the 
arterial  tension  to  the  lowest  point,  and  increases  greatly  the  action 
of  the  heart,  a  necessary  result  of  the  enormous  dilatation  of  the 
peripheral  vessels.  The  reflex  and  spinal  effects,  the  cardiac  and 
arterial  disturbance,  are  the  opposite  of  those  produced  by  strychnia. 
From  the  physiological  standpoint,  then,  an  antagonism  must  be 
presumed  to  exist  between  them.  An  experimental  research  by 
Dr.  Gray,*  of  Glasgow,  strongly  supports  this  view.  Thus,  he 
found  that  one  fourth  of  a  grain  of  strychnia  proved  fatal  usually  to 
the  rabbits  which  he  used  for  experiment.  He  was  able  to  admin- 
ister half  a  grain  of  strychnia  and  ten  drops  of  the  nitrite  of  amyl 
simultaneously,  by  subcutaneous  injection,  without  any  marked 
disturbance  following.  Of  course,  further  investigations  are  neces- 
sary, but  sufficient  is  now  known  to  justify  the  inhalation  of  nitrite 
of  amyl  in  cases  of  strychnia  poisoning. 

An  antagonism  to  a  limited  extent  has  been  discovered  by  Dr. 
Fothergill  between  aconite  and  digitalis.  The  rate  at  which  these 
agents  are  diffused  throughout  the  organism  differs  so  widely  that 
it  is  necessary,  in  order  to  display  the  antagonism,  to  administer  the 
digitalis  from  five  to  nine  hours  before  the  aconite.  Besides  the  in- 
teresting fact  of  the  antagonism,  this  subject  is  important  because 
of  the  additional  light — if  additional  light  were  needed — thrown  on 
the  actions  of  digitalis.  In  some  of  Dr.  FothergilPs  experiments, 
"  aconite  was  given  to  frogs  with  their  hearts  contracted  by  digitalis ; 
in  others,  digitalis,  where  the  heart  was  paralyzed  by  aconite.  The 
aconite  did  not  exercise  a  very  marked  effect  upon  the  hearts  con- 

*  "  Glasgow  Med.  Jour.,"  1871,  p.  188. 


DIGITALIN   AND    SAPONIN.  83 

tracted  by  digitalis,  but  the  other  experiment  was  more  success- 
ful. .  .  .  Slowly  and  gradually  the  distended  ventricle  recovered 
itself  under  the  action  of  digitalis,  the  contractions  being  more 
rhythmical  and  perfect,  and  the  distention  less  and  less  pronounced, 
until  a  return  to  normal  was  brought  about."  A  lethal  dose  of 
aconitin  was  antagonized  in  rabbits  by  digitalin  given  a  sufficient 
time  before.  This  slowness  in  the  action  is  a  well-recognized  qual- 
ity of  the  remedy,  and  its  elimination  from  the  organism  seems 
equally  tardy. 

Between  digitalin  and  saponin  an  antagonism  of  considerable 
extent  has  been  traced  by  Kohler.*  Saponin  being  comparatively 
little  known,  some  account  of  its  origin  and  actions  may  be  a  neces- 
sary preliminary.  Saponin  is  a  glucoside,  obtained  from  sapona- 
ria  officinalis.  It  has  close  relationship  to  our  indigenous  polygala 
senega,  and  the  active  principle,  senegin,  which  is  probably  the  same 
as  Quevenne  and  Procter's  polygalic  acid,  is  the  same  in  composi- 
tion as  the  glucoside  principle,  saponin. f  The  important  actions 
of  saponin  are  its  irritating  effects  on  the  mucous  membrane,  pro- 
ducing violent  sneezing  when  applied  to  the  nose ;  its  power  as  a 
cardiac  poison,  arresting  the  heart  in  diastole;  and  its  activity  as  a 
muscular  poison  in  general.  Locally,  it  has  the  effect  of  arresting 
the  heart.  Owing  to  the  difference  in  the  rate  of  movement,  the 
antagonism  is  exerted  after  the  time  requisite  to  develop  the  activity 
of  digitalin.  A  heart  arrested  by  saponin  will  be  started  by  digi- 
talin, and  vice  versa.  Further  investigation  of  saponiu,  as  against 
atropia  and  strychnia,  will  doubtless  develop  very  interesting  facts. 

To  round  off  and  complete  the  study  of  digitalis,  I  should  not 
fail  to  mention  the  investigations  of  Boehm  in  regard  to  the  antago- 
nism between  this  agent,  on  the  one  hand,  and  muscaria  and  aco- 
nite on  the  other.  Boehm  found  that  when  the  heart  was  arrested 
by  digitalis  it  was  restored  to  action  again  by  the  administration  of 
muscaria  and  aconite.  Digitalis  acts  chiefly,  as  has  been  pointed 
out,  by  stimulating  the  apparatus  of  inhibition ;  muscaria  and  aco- 
nite affect  this  apparatus  in  the  opposite  way,  relaxing  the  grip,  as 
it  were,  of  the  inhibition,  and  permitting  freedom  of  movement.  I 
think  you  must  agree  with  me  that  these  studies  are  of  great  impor- 
tance, if  they  had  no  other  purpose,  in  illustrating  the  action  of 
digitalis,  and,  indeed,  the  mechanism  of  the  cardiac  movements. 


"Arch.  f.  exp.  Pathol.  u.  Pharmacol.,"  i,  p.  138. 
"  Die  Pflanzenstoffe,"  p.  750. 


84  PHYSIOLOGICAL   ANTAGONISM. 

A  very  interesting  cardiac  poison,  in  regard  to  which  but  little 
is  known,  is  phytolacca  decandra.  This  agent  arrests  the  heart  in 
diastole,  and  long  before  the  motor  and  reflex  functions  and  the 
respiration  have  ceased.  The  sensibility  of  the  sensory  nerves  is 
lessened  by  poke,  but  the  irritability  of  the  motor  nerves  and  the 
contractility  of  the  muscles  are  not  impaired  by  it.  It  is  a  spinal 
paralyzer.  The  power  to  arrest  the  heart  is  due  to  a  paralyzing 
action  on  the  motor  ganglia,  but  it  also  affects  the  cardiac  muscle. 
When  the  heart  is  arrested  by  the  fluid  extract,  and  some  portion  of 
it  is  allowed  to  come  in  contact  with  the  heart  itself,  the  paralysis 
is  so  complete  that  no  form  of  irritation,  including  a  strong  faradaic 
current,  can  arouse  it  to  action  again.  The  heart  thus  remains 
insensible,  when  the  muscles  everywhere  respond  energetically  to 
the  faradaic  stimulation.  More  slowly,  but  finally  as  completely, 
is  the  heart  paralyzed  by  the  injection  of  the  fluid  extract  into  any 
part  of  the  body.  Respiration  ceases,  with  paralysis  of  the  muscles, 
long  after  the  heart  has  stopped  its  beat. 

I  find  that  atropia  antagonizes  these  effects  of  phytolacca  com- 
pletely. It  maintains  the  cardiac  action,  so  that  lethal  doses  of 
poke  do  not  prove  fatal  when  administered  with  atropia.  The 
mechanism  is  obvious.  Atropia  stimulates  the  accelerator  nerves 
of  the  heart  and  the  motor  ganglia  in  the  muscular  substance ;  phy- 
tolacca exerts  a  paralyzing  action  on  the  same  apparatus.  The 
antagonism  is  exerted  not  only  when  they  are  simultaneously 
administered,  but  when  the  second  is  given  after  an  interval  of 
fifteen  minutes.  The  number  of  experiments  made  was  twenty, 
and  included  both  cold-  and  warm-blooded  animals. 

I  have  recently  conducted,  and  am  still  engaged  on,  an  elaborate 
series  of  experiments  with  mscum  album,  the  mistletoe,  for  the 
study  of  its  physiological  actions  and  its  antagonists.  It  is  a  cardiac 
tonic,  and  exalts  the  vascular  tension.  The  sensibility  of  the  sen- 
sory nerves  is  much  diminished  by  it,  but  the  irritability  of  the 
motor  nerves  is  not  impaired.  The  cardiac  and  respiratory  depress- 
ants are  its  antagonists,  especially  such  as  aconite  and  veratrum 
viride.  Further  researches  promise  interesting  disclosures. 

In  discussing  the  question  of  the  antagonism  of  chloral  and 
strychnia,  I  incidentally  alluded  to  the  cases  of  strychnia  poisoning 
treated  by  chloroform  or  ether  inhalations.  I  ought  not  to  conclude 
this  part  of  my  subject  without  some  references  to  this  topic.  The 
anaesthetics  suspend  the  reflex  functions  of  the  spinal  cord,  and 
cause  death  by  the  final  arrest  of  respiration  and  circulation.  They 


ANTAGONISMS    OF   ANAESTHETICS.  85 

are  therefore  antagonistic  to  those  remedies  which  exalt  the  reflex 
functions — as  strychnia,  brucin,  thebaia,  picrotoxine,  etc.  Ten  cases 
of  strychnia  convulsions  treated  successfully  by  the  inhalation  of 
ether  or  chloroform  are  reported.  The  anaesthetic  suspends  the 
heightened  sensibility,  and  thus  maintains  the  functions  which, 
would  otherwise  be  over-stimulated  until  the  elimination  of  the 
poison  is  accomplished.  What  is  true  of  the  treatment  of  strychnia 
poisoning  is  also  true  of  poisoning  by  the  other  agents  acting  simi- 
larly. The  antagonism  of  the  anaesthetic  group  with  the  tetanizing 
group  of  remedial  agents  is  therefore  supported  by  experimental 
and  clinical  evidence. 

With  the  antagonisms  discussed  in  this  lecture,  rather  hastily,  as 
the  limits  of  the  course  will  permit  no  fuller  treatment,  I  close  this 
part  of  the  subject — or  the  antagonism  between  medicines.  I  have 
yet  to  discuss,  in  the  remaining  lectures,  that  large  and  important 
practical  subject — the  antagonism  between  remedies  and  diseases. 
In  my  next  lecture,  I  shall  therefore  begin  the  consideration  of  this 
topic,  which  will  not  only  enforce  the  lessons  derived  from  the  study 
of  the  physiological  antagonisms  between  medicines,  but  will,  I 
hope,  demonstrate  a  path  which  we  may  surely  follow  in  the  treat- 
ment of  many  diseases. 


LECTUEE  Y. 

THE   ANTAGONISM   BETWEEN   REMEDIES   AND   DISEASES. 

SOME  diseases  are  cured  by  contraries,  was  the  aphorism  of  Hip- 
pocrates, but,  he  was  also  wise  enough  to  add,  some  are  cured  by 
similars.  It  was  obvious  enough,  even  at  that  remote  time,  that  no 
single  law  or  dogma  could  include  all  the  varied  conditions  of  dis- 
ease. The  doctrine  or  law  of  antagonisms  is  necessarily  applicable 
only  to  the  state  of  physiological  pathology — if  I  may  be  permitted 
such  a  phrase — and  not  to  structural  pathology,  unless  remediable 
by  physiological  processes.  For  example,  the  pathological  state  in- 
duced by  fl  uxionary  hypersemia  may  be  removed  by  agencies  acting 
on  the  vessels  in  the  opposite  way.  A  cachexia  or  diathesis,  as  the 
cancerous  or  tubercular,  sclerosis  of  organs,  etc.,  can  not  be  affected 
by  opposed  or  similar  remedies,  yet  some  important  symptom, 
occasioned  thereby,  may  be  acted  on,  as,  for  instance,  fever,  which 
may  be  subdued  and  its  ill  effects  prevented  by  the  proper  use  of 
some  antagonist  to  the  fever  process. 

The  limits  being  thus  set  to  our  inquiry,  we  may  proceed  to  in- 
vestigate the  nature  and  extent  of  the  antagonism  which  may  exist 
between  a  remedy  and  a  disease,  or  between  the  actions  of  a  remedy 
and  the  symptoms  of  a  disease.  As  the  antagonism  between  reme- 
dies has  been  treated  mainly  in  the  historical,  order,  it  will  be  best 
to  begin  with  the  first  historical  example  of  the  treatment  of  a  symp- 
tom of  a  diseased  state  by  its  physiological  antagonist — the  treat- 
ment of  paralysis  by  strychnia. 

STRYCHNIA   AND   PARALYTIC    STATES. 

As  I  have  already  shown,  we  owe  our  present  knowledge  of 
Strychnia  to  the  labors  of  Magendie,  whose  research  was  so  thor- 


STRYCHNIA   AND   PARALYTIC    STATES.  87 

ough  that  subsequent  investigators  have  been  able  to  add  but  little 
to  his  results.  This  pioneer  investigation — the  parent  of  all  the  im- 
portant work  which  has  since  been  done  in  this  field — is  a  striking 
illustration  of  the  permanence  of  the  results  thus  obtained,  and  is  in 
strong  contrast  with  the  variable  and  fleeting  opinions,  the  product 
of  empirical  methods.  Fouquier  and  Magendie,  recognizing  the 
opposition  of  actions  between  the  new  poison  and  paralysis,  pro- 
posed to  prescribe  it  when  suitable  cases  occurred,  but  Fouquier  had 
the  good  fortune  to  meet  with  suitable  cases  before  the  discoverer. 
Since  that  trial  of  strychnia  has  occurred  all  the  known  experience 
with  this  important  agent.  Strychnia  exalts  the  reflex  functions  of 
the  spinal  cord,  and  is,  therefore,  properly  the  antagonist  of  those 
conditions  of  disease  in  which  this  function  is  weakened.  Strych- 
nia also  energizes  the  heart  and  raises  the  arterial  tension,  by  stimu- 
lating the  vaso-motor  system,  and  therefore  opposes  all  actions  from 
disease  of  a  contrary  kind.  Strychnia,  further,  is  a  powerful  stimu- 
lant of  the  respiratory  function,  and  causes  death  by  asphyxia — by 
so  stimulating  the  muscles  of  respiration  that  they  become  tetani- 
cally  contracted,  and  is,  therefore,  the  antagonist  of  those  symptoms 
indicating  respiratory  depression.  Let  us  see,  now,  how  nearly 
clinical  experience  with  this  remedy  corresponds  to  the  deductions 
of  theory.  Diphtheritic  paralysis  is  an  excellent  illustration  and 
type  of  the  paralysis  to  which  the  action  of  strychnia  is  opposed.  It 
is  largely  a  functional  paralysis.  Although  some  structural  changes 
have  been  made  out  in  the  spinal-nerve  roots,  they  are  remediable 
under  the  changed  conditions  wrought  by  an  antagonistic  medicine. 
No  one  will  dispute,  I  think,  that  strychnia  is  the  most  important 
remedy  for  this  disease,  and  that  improvement  promptly  follows  on 
its  administration.  Furthermore,  it  is  obvious  that  strychnia  will 
produce  the  better  results,  the  more  it  is  concerned  with  sound  tis- 
sues. Hence,  measures  to  improve  the  nutrition  of  the  body  will 
increase  the  utility  of  strychnia. 

The  so-called  reflex  paralyses  are  clearly  antagonized  by  strych- 
nia, and  they  are  especially  benefited  by  its  administration.  It  is 
probable  that  reflex  paralyses  are  often  due  to  anaemia  of  the  motor 
center,  which  ceases  to  act  because,  reflex  impressions  causing  strong 
contraction  of  the  arterioles,  the  amount  of  blood  normal  to  the  part 
is  no  longer  received  by  it.  That  strychnia  produces  rather  a  hy- 
persemic  state  of  the  cord  and  motor  centers  generally,  while  it  also 
stimulates  them  to  greater  activity,  can  hardly  be  denied. 

The  power  of  strychnia  to  give  energy  to  the  cardiac  movements 


88          ANTAGONISM   BETWEEN    REMEDIES    AND    DISEASES. 

and  to  raise  the  arterial  tension  is  not  made  use  of  in  medical  prac- 
tice as  it  should  be.  Degenerative  changes  in  the  cardiac  muscle 
and  coincident  low  tension  of  the  vascular  system  are  conditions 
antagonized  by  strychnia  in  the  weak  heart.  Exhausting  haemor- 
rhage, the  action  of  the  heart  being  weak  and  the  vascular  tension 
low,  also  is  a  combination  to  which  the  action  of  strychnia  is  op- 
posed. I  find  that  Fordyce  Barker*  gives  nux  vomica  tincture  in 
considerable  doses,  in  conjunction  with  ergot,  for  the  arrest  of  post- 
partum  haemorrhage.  The  effect  of  nux  vomica  is  most  appropriate, 
because  so  exactly  antagonistic  to  the  conditions  present ;  it  stimu- 
lates the  cardiac  and  respiratory  centers,  and,  by  raising  the  tension 
in  the  vessels,  checks  the  flow  of  blood. 

Modern  experience  has  in  a  similar  way  made  use  of  strychnia  in 
the  treatment  of  depressed  states  of  the  respiratory  organs,  by  a  merely 
empirical  method.  The  wide-spread  popularity  of  Aitken's  phos- 
phate of  iron,  quinine,  and  strychnia,  not  only  as  a  general  tonic, 
but  as  a  remedy  for  incipient  phthisis,  is  due  largely  to  the  constit- 
uent strychnia.  It  has  come  to  be  recognized  that  strychnia  is  a 
respiratory  stimulant,  and  of  special  utility  in  chronic  bronchitis, 
in  asthma  from  paresis  of  the  diaphragm,  and  in  emphysema  with 
dilated  right  cavities  of  the  heart. 

SPASM  AND  THE   PAKALYZERS. 

The  relation  in  which  strychnia  stands  to  paralysis  is  comparable 
to  that  of  the  paralyzing  agents  to  spasm  and  cramp.  The  first 
physiological  research  to  determine  the  existence  of  muscular  irrita- 
bility was  the  memorable  study  of  woorara  by  Bernard.  This  is 
the  only  remedy  which  has  apparently  exerted  a  curative  influence 
on  hydrophobia.  Woorara — or  one  form  of  the  poison  possessing 
these  properties — destroys  the  irritability  of  the  end  organs  of  the 
nerves  in  the  muscles,  leaving  the  muscles  themselves  intact.  But 
it  also  depresses  and  suspends  the  reflex  functions  of  the  spinal 
cord,  and  paralyzes  respiration.  Hydrophobia  produces  symptoms 
in  opposition  to  these,  and  hence  they  should  cease  on  the  exhibition 
of  woorara.  Unfortunately  for  any  certainty  in  results,  this  agent 
varies  much  in  composition,  and  in  hydrophobia  a  peculiar  virus  is 
present,  which  does  not,  apparently,  diffuse  out  of  the  blood,  but 
continues  in  action,  death  occurring  from  exhaustion,  if  not  from 
the  spinal  effects  of  the  poison.  That  two  well-defined  cases  of 

*  "  The  Puerperal  Diseases."    New  York,  1874. 


SPASM   AND    THE   PAKALYZEKS.  89 

hydrophobia  should  get  well  during  the  administration  of  woorara 
affords  us  reason  to  hope  that  better  results  may  be  obtained  here- 
after from  a  more  uniform  and  stable  preparation,  or  from  a  new 
agent  acting  similarly.  Tetanus  is  a  better  type  of  a  spasmodic 
disease  than  hydrophobia.  NO  similitude  in  the  action  of  a  remedy 
and  the  symptoms  of  a  disease  can  be  greater  than  between  strych- 
nia and  tetanus,  and  this  resemblance  extends  to  their  behavior 
under  the  influence  of  opposing  remedies.  As  the  tetanic  symp- 
toms produced  by  tetanus  proceed  from  a  peripheric  irritation — a 
wound — and  those  due  to  strychnia  are  the  result  of  an  impression 
made  through  the  blood  on  the  center — the  cord,  receiving  simulta- 
neously two  impressions  from  different  sources,  should  be  strongly- 
inhibited  and  the  impressions  neutralize  each  other.  Such  would 
be  an  adequate  explanation  of  the  result,  if  tetanus  were  cured  by 
strychnia.  As  it  is  not,  we  have  a  striking  illustration  of  the  falla- 
cies in  the  ancient  doctrine  of  similars.  There  are  six  remedies 
which  have  been  used  with  success  in  the  treatment  of  tetanus: 
chloroform  by  inhalation,  chloral,  tobacco  or  its  alkaloid  (nicotin), 
bromide  of  potassium,  physostigma,  and  gelsemium.  How  much 
soever  these  agents  may  differ  in  other  points  of  action,  they  agree 
in  the  power  to  diminish  or  suspend  the  reflex  functions  of  the 
spinal  cord.  They  therefore  act  in  opposition  to  this  distinctive 
symptom — an  aggravated  reflex  sensibility.  The  success  which 
attends  the  administration  of  these  agents  is  not  the  same,  since 
they  differ  in  the  exactitude  with  which  they  oppose  the  morbid 
complexus.  In  poisoning  by  strychnia,  the  same  group  of  remedies 
comes  into  use.  Chloral,  as  we  have  seen,  is  a  very  efficient  antag- 
onist, and  the  inhalation  of  chloroform  seems  equally  so. 

When  the  convulsions  are  of  the  epileptiform  type,  some  antag- 
onists that  have  a  similarity  of  action,  and  also  some  acting  in  the 
opposite  way,  are  employed.  Picrotoxine  represents  the  former,  and 
potassium  bromide  the  latter.  In  epileptiform  seizures,  an  abnormal 
excitability  of  Nothnagel's  spasm  center  may  be  presumed  to  exist, 
and  hence  those  agents  acting  against  clonic  convulsions  must  have 
the  power  to  diminish  this  abnormal  excitability.  Agents  having  a 
similarity  of  action  stimulate  the  spasm  center,  but,  as  inhibition 
results  when  two  impressions  coming  frpm  different  points  are 
made  on  the  spinal  cord  simultaneously,  so  here  quiescence,  or  the 
normal  equilibrium,  is  the  result,  when  the  disease  impression  and 
the  medicine  impression  act  on  the  spasm  center  at  the  same  time. 
As  picrotoxine  rather  increases  cerebral  hypersemia,  if  it  exist,  and 


90          ANTAGONISM   BETWEEN    KEMEDIES    AND   DISEASES, 

promotes  the  intra-cranial  circulation  when  weak  or  deficient,  it  is 
obviously  adapted  to  those  states  characterized  by  anaemia  and  de- 
pression. On  the  other  hand,  bromide  of  potassium  produces  its 
best  effects  when  the  subject  rather  tends  to  plethora,  and  when  the 
intra-cranial  circulation  is  too  active.  No  fact  with  regard  to  the 
action  of  bromide  of  potassium  is  more  distinctive  than  its  power 
to  arrest  symptomatic  or  epileptiform  convulsions  due  to  the  pres- 
ence of  a  neoplasm.  When  a  tumor  develops  in  the  brain,  there  is- 
always  present  a  very  considerable  degree  of  cerebral  hyperaemia. 
The  abnormal  excitability  of  the  spasm  center  may,  indeed,  be 
chiefly  due  to  -this  increased  blood  supply,  inducing  an  excessive 
functional  activity.  Although  under  such  circumstances  the  con- 
vulsions are  prevented,  no  modification  of  the  disease  is  effected— 
an  illustration  of  a  fact  that  the  antagonism  is  exerted,  if  at  all,  be- 
tween a  symptom  produced  by  the  disease  and  a  symptom  produced 
by  the  remedy,  although  the  cause  of  the  disease  symptom  may 
continue  unaffected  by  the  remedy.  During  the  administration  of 
the  bromides  in  epilepsy,  the  condition  of  the  faucial  reflex  affords- 
an  indication  of  the  state  of  .the  spasm  center.  Thus,  Yoisin  haa 
shown  that,  when  no  movement  is  caused  by  touching  the  base  of 
the  tongue,  the  pillars  of  the  fauces,  and  the  walls  of  the  pharynx, 
the  effect  of  the  bromides  is  sufficient.  A  capital  application  of  the 
principle  of  antagonism,  as  exhibited  in  the  opposition  of  the  action 
of  a  medicament  to  an  important  symptom  of  a  disease,  is  the  use 
of  the  nitrite  of  amyl  to  abort  the  epileptic  paroxysm.  It  is  known 
to  all  here  present,  of  course,  that  the  epileptic  paroxysm  is  inaugu- 
rated by  a  sudden  deathly  pallor,  in  which  the  arterioles  of  the  brain 
are  strongly  contracted,  and  an  extreme  degree  of  anosmia  is  in- 
duced. Then  follows  the  tetanic  stage,  with  suspension  of  respira- 
tion and  cyanosis.  By  the  timely  inhalation  of  amyl  nitrite,  these 
phenomena  may  be  prevented  and  the  fit  aborted.  No  sooner  is  a 
whiff  of  the  vapor  inhaled  than  the  arterioles  are  dilated,  and  a 
bright  flush  takes  the  place  of  the  pallor,  the  stage  of  rigidity  does 
not  come  on — in  fact,  the  epileptic  paroxysm,  which  was  imminent, 
fails  to  develop. 

The  principle  of  antagonism  applies  equally  to  the  treatment  of 
chorea.  The  most  successful  treatment  is  that  having  for  its  ob- 
jects the  maintenance  of  a  quiescent  state  of  the  motor  centers  and 
the  prevention  of  those  irregular  discharges  of  nervous  force  which 
constitute  the  physiognomy  of  the  malady.  Those  who  maintain 
that  quiet,  repose,  the  absence  of  all  possible  sources  of  excitement, 


SPASM    AND    THE   PAEALYZEES.  91 

are  sufficient  for  the  cure,  are  seeking  to  accomplish,  by  merely  hy- 
gienic means,  the  same  end  which  those  are  pursuing  who  admin- 
ister calmative  medicines.  By  chloral,  by  the  large  doses  of  mor- 
phia prescribed  by  Trousseau,  by  cimicifuga,  by  conium,  etc.,  the 
excitability  of  the  motor  centers  is  lessened ;  in  other  words,  the 
mobile  state  of  the  nerve  matter  is  opposed  by  agents  which  lessen 
and  finally  suspend  all  motor  activity. 

In  certain  neuroses  of  the  respiratory  and  circulatory  organs^ 
the  phenomena  of  antagonism  are  exhibited  in  perfection.  Here, 
indeed,  is  an  embarrassment  of  riches.  We  are  concerned  at  pres- 
ent with  those  disturbances  of  functions  characterized  by  the  occur- 
rence of  spasm  or  cramp.  In  this  category  are  included  paroxysmal 
cough,  cough  by  habit,  hiccough,  whooping-cough,  spasmodic  asthma, 
angina  pectoris,  etc.  Cough,  as  everybody  knows,  is  a  reflex  act,  in. 
which  many  parts  participate  besides  the  breathing  organs.  Experi- 
mental evidence  coincides  with  the  clinical  in  fixing  on  the  bronchi 
as  the  seat  of  the  maximum  excitability  to  this  reflex  act,  and  es- 
pecially at  the  bifurcation  of  the  trachea,  according  to  experiments. 
Let  us  take  laryngismus  stridulus  for  illustration.  Irritation  of  the 
sensory  filaments  of  the  pneumogastric  in  the  mucous  membrane, 
transmitted  to  the  nucleus,  is  reflected  over  the  motor  branches,  and 
the  muscles  are  thrown  into  cramp.  Hence  the  resounding  cough. 
To  prevent  this  reflex  act  is  the  object  o'f  treatment,  and  those 
agents  having  this  power — chloral,  bromide  of  potassium,  nause- 
ants,  etc. — promptly  relieve  the  spasm.  Cough  maintained  by 
habit,  whooping-cough,  and  paroxysmal  coughs  are  effectually 
treated  only  by  those  remedies  which  oppose  the  exaggerated  re- 
flex excitability,  such  as  .hydrocyanic  acid,  gelsemium,  conium, 
morphia,  chloral,  etc.  Spasmodic  asthma  affords  a  superior  oppor- 
tunity for  the  trial  of  the  various  motor  and  reflex  depressants — the 
antagonists  of  the  disease  symptoms.  The  inhalation  of  ether,  the 
subcutaneous  injection  of  morphia,  belladonna,  tobacco,  grindelia, 
faradism  or  galvanism,  are  used  as  antagonists  with  more  or  less- 
success,  but  the  selection  of  an  antagonist  is  necessarily  involved  in 
obscurity,  owing  to  the  uncertainty  which  still  surrounds  the  mech- 
anism of  the  asthmatic  paroxysm. 

Singultus,  or  hiccough,  affords  us  an  apt  illustration  of  both 
modes  of  antagonism — by  similarity  and  by  opposition.  In  singul- 
tus,  a  recurring  spasm  of  the  diaphragm  is  supposed  to  be  the  con- 
dition. I  have  already  shown  that  this  disease  may  be  arrested  by 
a  spasm-inducing  agent — a  rapidly  interrupted  faradaic  current.  If 


92         ANTAGONISM   BETWEEN    REMEDIES    AND    DISEASES, 

a  strong  current  be  passed  at  the  moment  the  spasm  is  to  take  place, 
it  is  entirely  aborted.  The  mechanism  has  been  explained  before, 
but  it  is  so  striking  an  exemplification  of  one  mode  of  inhibition 
that  it  will  bear  repetition.  The  reflex  spasm  does  not  take  place, 
because  of  the  strong  irritation  of  the  peripheral  fibers,  inducing  in- 
hibition. The  remedies  acting  by  opposition  are  those  which  lessen, 
and  suspend  reflex  action,  as  the  anaesthetics,  morphia,  bromides, 
amyl  nitrite,  chloral,  etc.  Another  admirable  illustration  of  antag- 
onism of  a  spasmodic  state,  and  at  the  same  time  an  example  of 
scientific  therapeutics,  is  the  treatment  of  angina  pectoris  by  the 
inhalation  of  amyl  nitrite.  We  owe  this  ingenious  suggestion  to 
Dr.  Lauder  Brunton,  who,  ascertaining  that  in  angina  pectoris  there 
ensued  sudden  strong  contraction  of  the  arterioles,  manifested  in 
pallor  of  the  surface,  small  strong  pulse,  labored  action  of  the  heart, 
etc.,  proposed  the  inhalation  of  amyl  nitrite  to  overcome  this  con- 
tracted state  of  the  vaso-motor  fibers ;  and  the  suggestion  has  been 
most  successful,  giving  prompt  relief  in  a  condition  of  imminent 
danger.  Sudden  contraction  of  the  arterioles  of  a  member,  of  the 
iingers,  or  other  part  of  the  body,  the  tissues  so  affected  appearing 
dead-white,  and  losing  their  sensibility,  occurs  in  young  girls  and 
in  women  at  the  climacteric  period.  Bromide  of  potassium  prompt- 
ly removes  this  state  by  relaxing  the  vaso-motor  fibers. 

PAIN   AND   THE    ANODYNES. 

The  same  principle  of  antagonism  obtains  in  the  treatment  of 
pain.  The  sensation  which  we  call  pain  is  composed  of  several  ele- 
ments :  of  the  peripheral  irritation,  the  transmission  of  the  impres- 
sion to  the  center,  and  its  realization  by.  consciousness.  It  follows 
that  pain  may  be  relieved  by  interrupting  its  transmission  to  the 
centers  of  conscious  impressions,  or  by  suspending  the  functions  of 
those  centers.  For  example,  aconite  and  gelsemium  relieve  pain  in 
the  former,  and  the  anaesthetics  in  the  latter  mode.  "When  aconite 
is  applied  to  the  peripheral  filaments  of  a  sensory  nerve,  the  power 
to  transmit  the  sensation  of  pain  is  gradually  extinguished,  and  in 
poisoning  by  aconite  there  is  ultimately  reached  a  condition  in  which 
no  pain  is  experienced  from  any  form  of  irritation.  Aconite  is  there- 
fore antagonistic  to  peripheral  neuralgia.  The  anaesthetics,  locally 
applied,  have  similar  effects,  arid  are  therefore  antagonistic  to  both 
centric  and  peripheral  neuralgia.  When  a  few  minims  of  chloro- 
form are  thrown  into  the  neighborhood  of  a  nerve  trunk,  the  pe- 
ripheral expansion  of  the  nerve  is  put  into  an  anaesthetic  and  analge- 


PAIN    AND    THE    ANODYNES.  93 

sic  state.  The  deep  injection  of  chloroform  for  sciatica,  cervico-bra- 
chial  neuralgia,  coccyodynia,  and  neuralgia  of  nerves  in  accessible 
situations,  is  an. expedient  of  the  highest  value.  Since  I  brought 
this  method  forward  a  few  years  ago,  I  have  had  a  large  experience 
of  its  use  in  sciatica,  neuralgia  of  the  infraorbital  and  supraorbital 
branches  of  the  fifth,  and  intercostal  and  cervico-brachial  neuralgia, 
and  can  reaffirm  with  emphasis  my  original  statements.  Some  for- 
eign experience  has  been  equally  favorable.  This  method  is  adapted 
more  especially  to  the  cases  of  some  weeks'  or  months'  duration,  and 
to  those — it  can  not  be  too  often  repeated — situated  in  nerves  acces- 
sible to  the  treatment.  To  inject  chloroform  under  the  integument, 
as  morphia  and  other  anodynes  are  injected,  is  simply  useless,  un- 
less the  affected  nerve  be  in  the  neighborhood.  This  expedient  is 
the  more  valuable,  since  no  danger  attends  its  use,  and  inflamma- 
tory indurations  and  abscesses  rarely  result.  The  most  powerful 
means  for  the  relief  of  pain  which  we  now  possess — the  hypoder- 
mic injection  of  morphia  and  atropia  combined — is  an  illustration 
of  the  utility  and  advantage  derived  from  the  study  of  physiological 
antagonism.  The  mutual  interactions  of  morphia  and  atropia  are 
such  that,  while  the  pain-relieving  power  is  not  impaired  but  en- 
hanced by  combination,  other  signal  disadvantages  of  each  are  com- 
pensated for  in  the  action  of  both.  Physiological  research  has 
further  shown  that  the  advantages  of  anaesthesia  are  promoted  by 
the  preliminary  injection  of  morphia,  and  that  "mixed  anaesthesia  " 
is  both  more  effective  and  safer.  Chloroform  certainly  should  not 
be  administered,  under  ordinary  circumstances  at  least,  without 
the  preliminary  injection  of  morphia  and  atropia.  A  sudden  death 
from  paralysis  of  the  heart,  in  a  case  of  ether  narcosis  which  hap- 
pened in  London  last  month,  ought  to  warn  us  in  regard  to  the  fan- 
cied security  against  cardiac  paralysis  from  ether  inhalation,  which 
Schiff  especially  has  inculcated.  We  ought  to  recognize  the  fact 
that  the  condition  of  anaesthetic  sleep  is  a  condition  of  danger, 
which  is  merely  relative  in  respect  to  the  agent  used,  and  employ 
antagonists  to  the  fatal  tendency — paralysis  of  heart  or  lungs.  The 
antagonist  on  which,  it  appears,  much  dependence  may  fairly  be 
placed  is  the  subcutaneous  injection  of  morphia  and  atropia.  The 
danger  which  attends  the  administration  of  chloral  may  be  to  a 
large  extent  averted  by  the  simultaneous  prescription  of  atropia,  as 
some  recent  cases  of  accident  unequivocally  show.*  I  several  year& 

*/'  Allg.  med.  Centr.-Zeitung,"  July  21,  1880. 


^94          ANTAGONISM   BETWEEN   KEMEDIES    AND    DISEASES. 

ago  demonstrated,  in  a  paper  read  before  the  Neurological  Society, 
of  New  York,  that,  while  morphia  and  bromide  of  potassium  in- 
tensified the  effects  of  chloral  in  every  way,  atropia  antagonized  the 
effects  on  the  heart,  and  would  thus  apparently  save  life  after  lethal 
doses.  I  then  also  called  attention  to  the  danger  of  the  combina- 
tion of  chloral  and  potassium  bromide  as  a  poison  to  the  heart, 
which  the  subsequent  experiments  of  Husemann  *  and  abundant 
clinical  experience  have  since  confirmed. 

MENTAL    STATES   AND   THEER   ANTAGONISTS. 

The  antagonism  of  a  mental  state  by  the  action  of  a  remedy 
implies  the  fact  that  the  mental  is  a  mere  symptom  of  a  physical 
condition.  Those  who  believe  otherwise  are  indeed  few  in  number, 
and  constantly  diminish  as  the  progress  of  our  means  of  minute 
research  develop  more  and  more  fully  the  dependence  of  symptoms 
on  lesions.  The  antagonism  of  insomnia  to  sleep-producing  medici- 
nal agents  is  conspicuously  demonstrated  in  the  action  of  chloral. 
Acute  delirious  mania,  and  acute  mania,  when  due  to  physiologico- 
pathological  states,  and  not  dependent  on  unchangeable  structural 
lesions,  are  antagonized  by  the  same  agent,  and  often  speedily  cured 
by  its  timely  exhibition.  High  excitement,  with  illusions  and  hal- 
lucinations, and  great  motor  activity,  are  antagonized  by  gelsemium, 
duboisia,  hyoscyamia,  conium,  and  other  remedies  acting  similarly. 
Melancholia,  with  torpid  movements  and  suicidal  notions,  is  an- 
tagonized by  morphia.  Acute  cerebral  congestion,  of  the  active 
form,  is  opposed  by  such  arterial  sedatives  as  aconite,  veratrum 
viride,  and  potassium  bromide ;  and  acute  congestion,  of  the  pas- 
sive form,  by  digitalis,  ergot,  etc.  Anaemia  of  the  brain  is  removed 
by  strychnia,  brucia,  atropia,  quinia,  arid  other  excitants.  It  fol- 
lows that  mental  changes  dependent  on  these  vascular  states  must 
be  largely  controlled  by  the  timely  use  of  the  appropriate  antago- 
nist. Closely  allied  to  those  conditions  is  that  state  of  the  vessels 
disposing  to  the  formation  of  miliary  aneurisms.  It  may  appear 
a  fanciful  speculation  to  suggest  that  these  changes  preparatory  to 
cerebral  haemorrhage,  or  affecting  the  nutrition  of  the  brain  unfa- 
vorably, may  be  retarded,  possibly  prevented,  by  the  early  use  of 
such  agents  as  ergot,  digitalis,  quinia,  chloride  of  barium,  etc.  Al- 
though the  nutritional  alterations  in  the  vessel  walls  precede  the 
formation  of  miliary  aneurisms,  the  progress  of  the  changes  is  pro- 

*  Loc.  cit.,  p.  335 ;  also  the  same  author,  in  "  Dtsch.  med.  Woch.,"  No.  36-39,  1880. 


CAEDIAC    REMEDIES    AND    DISEASES.  95 

moted  by  the  relaxation  of  the  muscular  layer.  Agents  which  im- 
prove the  vascular  ton  us  have,  therefore,  the  important  action  of 
retarding  the  nutritive  changes. 

CARDIAC   REMEDIES   AND   DISEASES. 

In  the  whole  pathological  field  there  are  no  more  perfect  illus- 
trations of  the  applicability  of  physiological  antagonism  to  the  thera- 
peutics of  disease  than  in  the  case  of  the  various  heart  maladies. 
The  most  exact  antagonism  has  been  shown  between  remedies  act- 
ing on  the  heart.  We  shall  now  see  similar  exactitude  in  the  an- 
tagonism between  remedies  and  diseases  of  the  heart.  Is  the  action 
of  the  heart  excessive  from  a  diminution  in  the  energy  of  the  inhibi- 
tion ?  We  have  remedies  to  oppose  this  state.  Is  the  heart  acting 
too  slowly  from  excess  in  the  inhibition  ?  We  have  remedies  to 
counteract  this  defect.  Is  the  heart  acting  too  rapidly  from  excess 
of  energy  descending  through  the  accelerator  nerves?  We  have 
remedies  to  diminish  the  production  of  this  energy.  Is  the  heart 
acting  feebly  from  a  paresis  or  weakness  of  the  accelerator  appara- 
tus ?  We  have  remedies  to  give  tone  and  increased  power  to  this 
apparatus.  Is  the  heart  acting  feebly  from  weakness  in  its  motor 
ganglia  ?  We  have  remedies  to  impart  strength.  Is  the  heart  act- 
ing too  violently  and  irregularly,  because  of  too  great  and  frequent 
discharges  of  force  ?  We  have  remedies  to  moderate  this  violence 
and  restore  the  rhythm.  Let  me  briefly  illustrate  these  points  in 
turn. 

In  that  singular  malady,  exophthalmic  goitre,  the  action  of  the 
heart  is  constantly  much  too  rapid,  and  is  often  exceedingly  so, 
from  the  diminution  in  the  inhibitive  control  of  its  movements. 
The  carotid  and  the  vessels  of  the  thyroid  gland  are  relaxed  and 
dilated,  and  hence  this  gland  may  pulsate  almost  like  an  aneurism. 
This  condition  of  things  is  the  essential  change.  It  is  true,  in  all 
advanced  cases  the  heart  is  the  seat  of  various  structural  alterations, 
but  these  are  not  necessary  to  constitute  the  disease.  If  exophthal- 
mic goitre  is  treated  by  the  antagonists  to  that  condition  of  the 
heart  and  vessels  before  the  structural  alterations  above  mentioned 
occur,  it  is  usually  curable.  These  remedies  are  galvanism  (to  the 
pneumogastric  and  cervical  sympathetic),  digitalis,  and  ergot,  which 
increase  the  inhibition  and  the  vascular  tension,  substituting  a  slow 
and  orderly  movement  for  the  wild  disorder  of  the  disease.  In 
some  maladies,  such  a  strong  inhibitive  influence  descends  along 
the  pneumogastric  that  the  heart  is  restrained,  tied  up,  and  its 


96          ANTAGONISM    BETWEEN    EEMEDIES    AND    DISEASES. 

movements  are  greatly  retarded ;  again,  the  heart  may  be  slowed 
by  agencies  paralyzing  the  accelerator  apparatus  or  the  motor  gan- 
glia. If  the  physician,  influenced  by  the  fact  of  the  slow  move- 
ment, prescribed  without  reference  to  the  mechanism,  he  might  da 
serious  mischief.  The  excess  of  inhibition  is  overcome  by  such  an 
agent  as  aconite,  which  depresses  the  function  of  the  inhibiting 
nerve ;  the  paralysis  of  the  accelerator  apparatus  or  of  the  motor 
ganglia  is  overcome  by  the  stimulants  of  these  organs,  of  which 
atropia  is  the  best  representative.  Palpitation  of  the  heart  may  be 
caused  by  irregular  and  explosive  discharges  of  nervous  force  com- 
ing from  the  accelerator  nerves,  or  from  paroxysmal  loss  or  depres- 
sion of  the  inhibition.  In  the  former  case,  such  an  agent  as  bro- 
mide of  potassium,  and  in  the  latter  as  digitalis,  is  required.  When 
the  action  of  the  heart  is  weak  from  depression  of  the  acceler- 
ator apparatus,  atropia  stimulates  this  apparatus  and  antagonizes 
the  conditions  which  result  from  it.  The  most  important  antago- 
nist to  states  of  depression  is  digitalis,  provided  certain  conditions 
are  observed.  I  ana  the  more  urgent  in  presenting  this  point  be- 
cause I  believe  the  use  of  digitalis  is  carried  much  too  far  in  the 
treatment  of  cardiac  weakness.  Digitalis  increases  the  inhibition, 
slows  the  heart  by  lengthening  the  diastolic  interval,  energizes  the 
heart  muscle,  and,  by  increasing  the  force  of  the  recoil,  favors  the 
passage  of  blood  into  the  coronary  artery.  Digitalis  also  raises  the 
arterial  tension.  Long-continued  medicinal  doses,  and,  in  a  very 
short  time,  lethal  doses,  exhaust  the  irritability  of  the  apparatus  on 
which  their  effects  are  expended.  In  a  case  of  poisoning,  reported 
by  Mazel,*  a  woman  of  twenty -five  died  of  paralysis  of  the  heart 
on  the  fifth  day  after  poisoning  by  digitalis,  her  pulse  meanwhile 
having  risen  from  40  to  65.  Traube  has  shown  that  large  doses  of 
digitalis  paralyze  the  pneumogastric,  and  hence  the  pulse  thus  be- 
comes exceedingly  rapid.  When  a  patient,  lying  recumbent,  is 
taking  a  course  of  digitalis,  the  pulse  may  be  reduced  to  40  a  min- 
ute ;  but,  on  assuming  the  erect  posture,  it  becomes  very  rapid  and 
weak.  The  practical  deductions  from  these  observations  are,  that 
digitalis  must  be  given  in  moderate  doses,  and  not  too  rapidly, 
owing  to  the  prolongation  of  its  effects.  In  the  condition  of  fatty 
heart,  its  use  is  more  than  doubtful,  owing  to  the  fact  that  it  de- 
cidedly increases  the  arterial  tension  and  thus  imposes  additional 
work  on  the  heart.  Digitalis  opposes  the  conditions  present  when 

*  "  Gaz.  des  Hop.,"  1864,  No.  74. 


CAKDIAC    EEMEDIES    AND   DISEASES.  97 

mitral  lesions  disturb  the  normal  work  of  the  heart.  The  organ  is 
weak  and  acts  quickly  from  relaxation  of  the  inhibition ;  the  arte- 
rial system  has  relatively  much  less  and  the  venous  system  much 
greater  than  the  normal  quantity  of  blood ;  the  arterial  tension  is 
low,  and  the  venous  tension  is  too  high,  relatively  and  absolutely. 
Digitalis  opposes  these  conditions  when  used  in  the  proper  quan- 
tity. It  increases  the  energy  of  the  cardiac  contractions,  readjusts 
the  distribution  of  blood  by  raising  the  tension  in  the  arterial  sys- 
tem and  by  increasing  the  power  of  the  heart  beats,  and  so  length- 
ening the  diastolic  interval  as  to  permit  more  blood  to  enter  the 
left  cavity.  Moderate  doses,  too  frequently  repeated,  or  large 
medicinal  doses,  will  exhaust  the  irritability  of  the  apparatus  on 
which  digitalis  acts,  and  it  will  then  cease  to  antagonize  the 
symptoms  against  which  it  was  prescribed. 

The  antagonism  between  remedies  and  disease  is  well  exhibited 
in  the  treatment  of  aneurism  by  medicinal  means.  By  slowing  the 
blood  current,  and  diminishing  the  caliber  of  the  peripheral  vessels, 
blood  coagulates  in  the  sac,  the  clot  organizes,  and  a  cure  is  effected. 
After  learning  the  success  of  Hildebrandt  in  curing  uterine  fibroids 
by  the  subcutaneous  injection  of  ergotine,  Langenbeck  bethought 
himself  of  the  treatment  of  aneurism  by  the  same  means.  His 
notion  appears  to  have  been  that  ergot,  causing  contraction  of  the 
muscular  fiber  of  the  aneurismal  walls,  gradually  compressed  the 
sac  and  thus  effected  a  cure.  It  has  been  urged,  accordingly,  that 
ergot  injections  could  be  of  no  use  in  cases  of  aneurism  of  the  aorta, 
since  this  vessel  contains  no  muscular  coat.  Those  making  this 
objection  are  apparently  unacquainted  with  the  fact  that  the  solidi- 
fication of  the  sac  is  caused  by  coagulation  of  the  blood  in  it,  and 
that  the  conditions  most  favorable  to  such  coagulation  are  a  slow 
action  of  the  heart  and  increased  tension  at  the  periphery — pro- 
duced by  the  injections  of  ergot.  In  the  arrest  of  haemorrhage  the 
same  principles  obtain.  Who  now  trusts  to  opium  and  acetate  of 
lead,  to  tannin,  to  sulphuric  acid,  and  the  medley  of  ancient  astrin- 
gents? Modern  pharmacological  research  has  placed  in  our  hands 
the  most  efficient  remedies — antagonists  to  the  conditions  producing 
haemorrhage.  Increased  action  of  the  heart  and  relaxation  of  the 
vessel  walls  are  the  conditions  to  be  antagonized  in  haemorrhage, 
and  the  most  effective  remedies  are  ergot,  digitalis,  potassium  bro- 
mide, veratrum  viride,  etc.  The  subcutaneous  injection  of  ergotine 
is  the  most  speedy  and  certain  means  of  arresting  pulmonary  haemor- 
rhage. Menorrhagia  is  usually  more  promptly  arrested  by  bro- 
7 


98          ANTAGONISM   BETWEEN    REMEDIES    AND    DISEASES. 

mide  of  potassium.  These  remedies  may  usually  be  given  in  com- 
bination :  bromide  of  potassium  and  digitalis  by  the  mouth ;  ergot 
subcutaneously.  The  application  of  cold  and  heat  in  the  arrest  of 
haemorrhage  is  based  on  the  same  principle.  Cold  causes  imme- 
diate contraction  of  the  arterioles,  but  relaxation  follows ;  heat,  on 
the  other  hand,  first  relaxes,  but  contraction  soon  follows,  and  is 
more  energetic  than  that  at  first  produced  by  the  contact  of  cold. 

RESPIRATION   REMEDIES   AND   DISEASES. 

The  function  of  respiration  is  affected  by  remedies  that  depress 
and  by  remedies  that  excite.  The  action  of  those  remedies  em- 
ployed against  the  neuroses  of  the  respiratory  organs  has  been 
sufficiently  elucidated.  As  regards  the  reme'dies  depressing  the 
respiratory  function,  it  is  sufficient  to  remark  that  the  only  purpose 
to  which  they  can  be  properly  applied  is  to  impose  rest  on  the 
breathing  organs,  by  diminishing  the  number  and  lessening  the 
excursions  of  the  respiratory  efforts.  Important  results  have  been 
claimed  from  the  use  of  conium  and  gelsemium  in  pneumonia,  but 
grave  doubts  must  exist  as  to  the  accuracy  of  the  observations.  In 
respect  to  the  stimulants  of  the  respiratory  function,  much  good 
results  from  their  timely  use.  Strychnia,  as  has  been  pointed  out, 
is  a  respiratory  stimulant  of  great  activity  and  of  much  value  in 
suitable  cases.  In  some  cases  of  emphysema  and  chronic  bronchi- 
tis, and  in  the  carbonic-acid  narcosis  due  to  respiratory  failure  in 
acute  pulmonary  affections,  it  is  antagonistic  and  of  special  utility. 
Probably  no  remedy  so  generally  prevents  the  reflex  nausea  and 
vomiting  of  consumption.  There  is  none  but  a  theoretical  warrant 
for  the  statement,  yet  it  seems  probable  that  much  good  might 
result  from  the  hypodermic  injection  of  strychnia  in  capillary  bron- 
chitis, when  hsematosis  is  suspended  and  carbonic-acid  narcosis 
comes  on,  and  in  pneumonia,  when  abortive  attempts  at  crisis  are 
made.  The  utility  of  strychnia  in  chronic  bronchitis  and  bron- 
chorrhcea  is  attested  by  an  immense  experience. 

Atropia  is  a  more  generally  useful  respiratory  stimulant  than 
strychnia.  It  is  much  employed  in  certain  neuroses  of  the  lungs, 
but  its  chief  utility  consists  in  its  power  to  increase  respiration 
when  depressed  from  a  variety  of  causes.  Atropia  not  only  stimu- 
lates the  respiratory  center,  but  it  diminishes  the  irritability  of  the 
sensory  nerves  of  the  lungs,  and  increases  the  circulation  through 
these  organs.  These  properties,  more  than  its  power  to  arrest  night- 
sweats,  must  be  the  secret  of  the  influence  possessed  by  it  over  the 


INTESTINAL,    SKIN,    KIDNEY,    AND    BLADDER    EEMEDIES.       99 

nutrition  of  the  lung.  In  many  cases  of  caseous  pneumonia,  before 
the  process  of  softening  and  extension  of  the  caseous  matter  has 
begun,  atropia  distinctly  benefits  the  local  lesions  and  improves 
the  general  state. 

INTESTINAL   REMEDIES   AND   DISEASES. 

The  action  of  antagonistic  medicines  is  well  exhibited  in  the 
diseases  of  the  intestinal  tube.  A  serous  diarrhoea  is  promptly 
arrested  by  belladonna.  Opium  suspends  intestinal  movements 
and  stops  secretion ;  it  therefore  relieves  conditions  of  an  opposed 
kind,  namely,  diarrhoea  and  dysentery.  Constipation  due  to  torpor 
or  paresis  of  the  muscular  layer  of  the  bowel  is  often  promptly 
cured  by  the  faradaic  current.  When  the  muscular  layer  is  paretic, 
and  secretion  is  deficient,  the  relief  afforded  by  opposing  agents 
is  very  remarkable.  The  agents  antagonistic  to  this  condition  of 
things  are  mix  vomica,  belladonna,  and  physostigma;  and,  if  given 
in  combination,  they  will  oppose  and  remove  it. 

REMEDIES   ACTING   ON   THE   SKIN. 

In  the  night-sweats  of  consumption,  atropia,  duboisia,  hyos- 
cyamia,  and  other  members  of  the  group  oppose  the  conditions 
present  and  dry  the  skin.  The  value  of  this  treatment  is  great 
because  of  the  immense  loss  of  material  taking  place  through  the 
skin.  Sometimes  the  remedies  acting  by  similarity,  as  Dover's 
powder,  pilocarpine,  picrotoxine,  etc.,  are  useful,  but  at  present  the 
only  indication  for  their  employment  is  the  failure  of  the  other 
agents.  The  remedies  acting  by  opposition  succeed  much  more 
frequently  and  permanently.  A  deficiency  in  the  amount  of  cuta- 
neous secretion  may  require  the  use  of  sudoriparous  medicines. 
Pilocarpine  stands  at  the  head  of  the  agents  of  this  class.  Picro- 
toxine has  considerable  power  as  a  sudorific,  but  it  is  far  inferior  to 
pilocarpine.  Local  sweating,  as  of  one  extremity,  of  one  side  of  the 
head,  or  elsewhere,  is  usually  arrested  by  the  local  application  of 
atropia  or  belladonna.  The  milk  gland,  being  a  sweat  gland  modi- 
fied and  enlarged  for  this  special  office,  is  acted  on  by  antagonists 
in  a  manner  similar  to  the  skin.  Pilocarpine  increases  the  flow  of 
milk  ;  atropia  diminishes  and  arrests  it. 

REMEDIES   ACTING  ON  THE   KIDNEYS   AND    BLADDER. 

The  functions  of  the  skin  and  kidneys  being  to  a  certain  extent 
vicarious,  the  activity  of  one  necessitates  a  diminution  in  the  ac- 


100       ANTAGONISM   BETWEEN    EEMEDIES    AND    DISEASES. 

tivity  of  the  other.  Those  remedies  acting  on  the  skin  antagonize 
the  stimulants  of  the  renal  secretion.  A  state  of  lessened  activity 
of  the  kidneys  is  opposed  by  those  agents  having  a  special  action  as 
diuretics.  Substances  excreted  by  the  kidneys  and  acting  as  irri- 
tants promote  the  urinary  discharge — as  copaiba,  cubebs,  turpen- 
tine, etc. — but  these  are  not  proper  antagonists.  Remedies  such  as 
digitalis  and  squill,  which  increase  the  pressure  in  the  renal  vessels,, 
and  also  directly  stimulate  the  secretion,  are  the  proper  antagonists 
to  the  state  of  diminished  activity.  Recent  investigations  tend  to 
show  that  diuretics  of  this  kind  do  not,  as  was  supposed  at  one  time, 
affect  the  kidney  tissues  unfavorably,  but  rather  retard  than  hasten 
chronic  changes.  Excessive  urinary  discharge,  as  in  diabetes  insi- 
pidus,  may  be  due  to  passive  cerebral  congestion,  of  a  limited  area 
— the  floor  of  the  fourth  ventricle,  for  example — and  then  is  checked 
by  such  an  agent  as  ergot,  which  acts  by  contracting  the  vessels. 

Yery  admirable  results  are  Obtained  in  vesical  irritability  by 
the  appropriate  and  timely  use  of  antagonists.  There  is  a  form  of 
vesical  irritability  in  women,  especially,  which  is  often  admirably 
relieved  by  the  use  of  tincture  of  cantharides.  In  this  form,  there 
occurs  an  excessive  intolerance  of  the  presence  of  urine  in  the  blad- 
der, but  the  mucous  membrane  is  unaffected  and  the  urine  is  unal- 
tered. Tincture  of  cantharides  induces  a  similar  irritability.  The 
mechanism  by  which  relief  is  effected  is  the  inhibitive  result  of  two 
impressions  on  the  geni to-spinal  center.  Two  bodies  can  not  occupy 
the  same  place  at  the  same  time,  and  two  impressions  coming  from 
different  points,  and  of  equal  volume,  neutralize  each  other.  If  the 
same  irritability  of  the  bladder  coincides  with  a  catarrh,  or  the 
presence  of  a  stone,  it  need  hardly  be  stated  that  cantharides  will 
not  afford  relief.  Furthermore,  the  dose  of  cantharides  tincture 
necessary  to  afford  relief  is  the  quantity  required  to  cause  some 
irritability  of  the  organ. 

The  treatment  of  nocturnal  incontinence  of  urine  is  most  effec- 
tive when  based  on  antagonism  of  action.  This  malady  serves  to 
illustrate  an  important  principle,  although  of  slight  importance 
itself.  To  give  a  presumed  antagonist  without  reference  to  the 
associated  conditions,  is  to  invite  failure. .  The  incontinence  may 
depend  on  weakness  and  relaxation  of  the  sphincter.  When  a 
certain  amount  of  urine  accumulates,  the  sphincter  is  unable  to 
withstand  the  pressure.  In  other  cases  the  mucous  membrane  is 
intolerant,  and  a  sense  of  fullness  is  communicated  to  the  center, 
and  an  impulse  originates  for  the  expulsion  of  the  urine,  the  act 


REMEDIES    ACTING    ON   KIDNEYS    AND    BLADDEE.          101 

occurring  in  a  dream.  This  state  is  often  connected  with  abnormal 
acidity  of  the  urine.  In  still  other  cases,  the  muscular  layer  of  the 
bladder  is  in  an  irritable  state,  and  energetic  contraction  ensues 
whenever  the  urine  accumulates  sufficiently.  For  the  first  condi- 
tion, the  most  usual  probably,  belladonna  and  ergot  are  the  proper 
antagonists;  for  the  second  condition,  bromide  of  potassium  and 
alkalies ;  and  for  the  third,  such  remedies  as  gelsemium,  conium, 
chloral,  etc.,  are  most  appropriate.  This  malady,  then,  demon- 
strates how,  in  the  search  for  antagonists,  we  must  carefully  study 
the  physiological  pathology  of  the  disease.  The  conditions  of  the 
disease  being  known,  the  character  of  the  remedy  should  follow. 

With  this  general  survey  of  the  organs  and  systems  of  the  body, 
I  conclude  the  first  part  of  the  second  division  of  my  subject.  In 
the  next  and  final  lecture  of  the  course,  I  have  to  discuss  the  most 
important  of  the  practical  relations  of  this  subject  to  the  treatment 
of  diseases,  namely,  the  application  of  the  principle  of  physiological 
antagonism  to  the  therapeutical  management  of  general  or  constitu- 
tional states. 


LECTUKE  VI. 

ANTAGONISM   BETWEEN   REMEDIES  .AND   DISEASES. 

IT  must  seein  evident  to  those  who  followed  my  last  lecture,  or 
who  have  given  any  independent  thought  and  investigation  to  the 
subject,  that  the  treatment  of  local  maladies  is  governed  largely  by 
the  principle  of  antagonism.  Is  this  principle  equally  applicable  to 
the  treatment  of  constitutional  states  ?  Are  there  any  proper  an- 
tagonists to  inflammation,  to  fever,  and  to  the  diatheses  and  the 
cachexise.  I  think  it  can  be  shown  that  such  antagonists  do  ex- 
ist, and  that  our  most  successful  therapeutical  measures  are  ap- 
plied in  these  maladies  in  accordance  with  the  principle  of  antag- 
onism. 

First,  as  to  the  treatment  of  inflammation.  In  what  does  this- 
process  consist  ?  Assuming  no  points  that  are  in  doubt,  inflamma- 
tion may  be  defined  to  consist  in  a  dilatation  (paresis)  of  the  vessel 
walls,  followed  by  stasis  of  the  blood ;  in  an  increase  of  the  number 
and  a  modification  of  the  character  of  the  white  blood-corpuscles, 
and  their  migration  from  the  vessels  into  the  surrounding  tissues  ; 
in  a  simultaneous  diapedesis  of  the  red  corpuscles;  in  an  increase 
and  change  of  character  of  the  fibrine  and  albumen  of  the  blood, 
and  their  exudation  within  the  area  of  inflammation;  in  the  diffu- 
sion of  the  salts  of  the  serum,  especially  the  chlorides,  into  the  in- 
flamed parts  ;  in  an  increased  multiplication  of  the  cellular  elements 
of  the  tissues,  in  consequence  of  the  increased  pabulum  furnished 
them ;  and  in  a  breaking  up,  dissociation,  and  granular  degenera- 
tion of  the  anatomical  elements  of  the  inflamed  tissues.  With  these 
changes  in  the  local  condition  is  associated  a  febrile  state,  charac- 
terized by  increased  action  of  the  heart,  diminished  tension  in  the 
vessels,  and  elevated  temperature.  No  single  remedy  can  antago- 
nize the  complexusof  symptoms  belonging  to  inflammation,  but  the- 


ANTAGONISTS   TO   INFLAMMATION.  103 

successive  steps  in  its  development  may  be  counteracted  by  agents 
having  effects  opposed  to  those  of  the  existing  phase  of  the  process. 
The  initial  change — the  preliminary  congestion — is  often  compared 
to  the  phenomena  which  ensue  when  the  cervical  sympathetic  is 
divided.  Such  a  comparison  is  of  limited  applicability,  since  in 
inflammation  not  only  do  the  vessels  dilate,  but  coincident  changes 
occur  in  the  blood  and  in  the  tissues.  It  follows,  therefore,  that 
the  remedies  which  prove  effective  at  the  onset  of  an  inflammation 
must  act  not  only  on  the  contractility  of  the  vessels,  but  also  on  the 
corpuscular  elements  of  the  blood,  for  immediately  on  the  occur- 
rence of  stasis  the  migration  of  the  white  corpuscles  and  the  diape- 
desis  of  the  red  begin.  There  are  two  remedies  of  special  value  at 
this  juncture,  and  three  others  of  secondary  utility.  Quinia  and 
morphia,  administered  together  in  sufficient  quantity  at  the  right 
moment,  will  often  suppress  a  beginning  inflammation.  Such  a 
statement  can  not  be  supported  by  any  positive  facts,  for  it  is  im- 
possible to  decide  whether  the  morbid  process  would  have  proceeded 
beyond  the  point  ifc  had  attained.  The  negative  facts  have  a  high 
degree  of  importance,  for,  if  these  remedies  fail  to  accomplish  the 
arrest  of  the  inflammation  when  applied  at  the  right  moment,  they 
are  not  true  antagonists,  or  the  antagonism,  if  exerted,  is  without 
influence  over  the  development  of  this  process.  There  is  need  of 
facts  on  this  point,  and  the  profession  should  on  every  suitable 
opportunity  try  the  truth  of  this  supposed  antagonism.  My  own 
conviction  is  that  it  exists,  and  that  failure  is  due  to  the  inoppor- 
tune application  of  the  remedies. 

A  statement  of  the  physiological  actions  of  these  agents  will 
indicate  the  nature  of  the  opposition.  Quinia  and  morphia,  if 
administered  together  in  quantity  sufficient  to  produce  their  full 
physiological  effects,  will  raise  the  tonus  of  the  arterioles,  check  the 
migration  of  the  white  corpuscles  and  the  outward  diffusion  of  the 
albumen,  fibrine,  and  salts,  and  arrest  the  amoebiform  movements 
and  the  subsequent  multiplication  of  the  white  corpuscles  .outside 
the  vessels.  I  have  already  pointed  out  that  morphia  possesses  the 
power  to  raise  the  vascular  tension  and  to  check  all  vital  processes, 
and  in  these  actions  we  have  an  explanation  of  its  powers  in  inflam- 
mations. Quinia  has  a  greater  range  of  action.  Modern  researches 
have  cleared  up  all  that  was  uncertain  in  regard  to  its  physiological 
effects,  and  have  explained  the  therapeutical  uses  formerly  known 
only  through  empirical  observation.  It  would  occupy  all  the  time 
at  my  disposal  to  discuss  the  physiological  powers  of  quinia  from 


104       ANTAGONISM   BETWEEN   EEMEDIES    AND   DISEASES. 

the  historical  and  critical  standpoint ;  hence  I  must  content  myself 
with  the  barest  statement  of  the  main  facts.  We  owe  chiefly  to 
Professor  Binz,  of  Bonn,  the  demonstration  of  the  activity  of  quinia 
as  a  poison  to  protoplasm  and  to  the  minute  forms  of  life.  It  is  to 
this  property  that  its  power  to  arrest  the  movements  and  other  vital 
acts  of  the  white  corpuscle  is  due..  The  possession  of  this  property 
may  also  serve  to  explain  the  curative  power  of  quinia  in  malarial 
fevers,  if  the  recent  discovery  of  the  bacillus  malarise,  by  Klebs  and 
Tomassi-Crudeli,  is  continued  by  further  investigations.  For,  if 
the  malarial  diseases  be  produced  by  the  reception  and  multiplica- 
tion of  these  minute  organisms  in  the  blood — as  is  now  known  to 
be  the  result  of  the  action  of  Obermeier's  parasite  in  relapsing  fever 
— the  agency  of  quinia  in  their  destruction  is  readily  explained.  To 
act  efficiently  as  a  protoplasmic  poison,  as  might  be  expected,  qui- 
nia must  be  given  in  large  doses.  Besides  this  property,  quinia,  as 
Binz  and  others  have  shown,  lessens  the  oxidizing  function  of  the 
blood.  Ranke,  and  afterward  Kerner  and  Strassburg,*  has  shown 
that  it  also  reduces  to  a  remarkable  extent — one  half — the  excretion 
of  urea  and  uric  acid.  As  urea  represents  the  oxidation  of  the  ni- 
trogenous tissues,  it  is  obvious  that  quinia  checks  this  oxidation. 
It  follows  from  these  considerations  that  quinia  antagonizes  the 
increased  heat  production,  the  migration  and  subsequent  multi- 
plication of  the  white  cells,  and  the  proliferation  of  the  proto- 
plasm of  the  tissues,  while  morphia,  by  raising  the  vascular  tonus 
and  lowering  the  work  of  the  heart,  tends  to  remove  the  conges- 
tion. 

The  other  agents,  having  less  important  relations  to  the  antag- 
onism of  the  inflammatory  process,  are  digitalis,  aconite,  and  vera- 
trum  viride.  While  these  agree  in  the  power  to  lower  the  circula- 
tion, they  differ  in  the  mode  of  accomplishing  this  object.  Digitalis 
slows  the  heart,  but  energizes  its  movements  and  raises  the  arterial 
tension.  It  also  depresses  the  temperature,  but  any  effect  it  has 
over  the  movements  and  changes  of  the  protoplasm  is  secondary  to 
its  effect  on  the  tension  of  the  vessels.  The  amoebiform  movements 
of  the  white  corpuscles  are,  of  course,  favored  by  a  relaxed  state  of 
the  vessel  walls,  and  hindered  by  a  higher  tension.  The  influence 
of  digitalis  on  temperature  is  very  evident,  but  it  ranks  far  below 
quinia  as  an  antipyretic.  Hence  it  is  rather  as  an  aid  to  quinia 
that  digitalis  is  used  than  as  the  chief  antipyretic.  Among  those 

*  "  Arch.  f.  exp.  Pathol.  u.  Pharmacol.,"  ii,  p.  343. 


ANTAGONISTS   TO    INFLAMMATION.  105 

•so  prescribing  digitalis  I  may  mention  Liebermeister.  A  manifest 
objection  to  the  administration  of  digitalis  against  the  initial  move- 
ments of  the  inflammatory  process  is  the  slowness  of  its  action. 
After  the  primary  disturbance  in  the  digestive  organs,  from  five  to 
ten  hours  elapse  before  the  characteristic  physiological  effects  fol- 
low. The  slow  diffusion  of  the  active  constituents  into  the  blood 
is  only  equaled  by  their  tardy  excretion,  for  in  one  reported  case  a 
patient  poisoned  by  digitalis  died  on  the  fifth  day  from  paralysis  of 
the  heart.  It  follows  that  this  agent  can  not  be  used  effectively 
against  the  first  stage  of  inflammation.  Aconite  behaves  differently 
from  digitalis.  It  reduces  the  power  of  the  heart,  and,  although  it 
also  lowers  arterial  tension,  the  amount  of  blood  reaching  the  in- 
flamed area  is  reduced  by  it.  Furthermore,  it  lessens  oxidation  by 
diminishing  the  work  of  the  lungs,  and  reduces  temperature,  partly 
because  less  blood  is  distributed  when  the  heart  is  working  under 
its  influence,  and  partly  because  the  supply  of  oxygen  reaching  the 
tissues  is  less.  Aconite  is  especially  indicated  when  the  arterial 
tension  in  general  is  high  and  hsematosis  is  active.  Yeratrum  viride 
possesses  powers  and  properties  very  similar  to  those  of  aconite ;  but 
it  more  distinctly  affects  the  heart,  and  less,  proportionally,  the  lungs. 
Its  agency  in  checking  inflammation,  like  that  of  aconite,  consists 
in  lessening  the  amount  of  blood  going  to  the  inflamed  part,  and  in 
the  diminution  of  oxidation.  The  good  effects  of  digitalis,  aconite, 
and  veratrum  viride  cease  with  the  occurrence  of  exudation,  for  then 
new  conditions  arise  which  they  can  in  no  way  oppose  or  remove. 

The  antagonists  to  the  second  stage  of  inflammation  must,  ne- 
cessarily, have  the  power  to  prevent  or  remove  the  products  of  in- 
flammation. The  remedies  antagonizing  these  new  conditions  are 
quinia,  chloral,  and  the  alkalies.  The  utility  of  quinia,  however, 
ceases  when  the  exudate  has  actually  formed.  Chloral  is  especially 
adapted  to  this  stage  of  the  inflammation :  it  diminishes  the  fever 
heat,  dissolves  exudations,  quiets  restlessness  and  delirium.  The 
possession  of  these  properties,  except  the  solvent  action  on  exuda- 
tions, i$  nowhere  disputed.  The  experimental  evidence  of  this  power 
to  dissolve  exudates  is  conclusive,  and  the  clinical  experience,  al- 
though limited  and  difficult  to  define,  seems  to  favor  the  belief  in 
its  existence.  It  is  obvious,  however,  that  the  points  of  contact 
between  chloral  in  the  blood  and  the  exudation  in  an  inflamed 
area  are  small.  It  must,  therefore,  be  more  effective  when  it  is  ad- 
ministered before  the  final  stasis  occurs.  The  influence  of  an  agent 
which  substitutes  quiet  for  delirium  is,  in  general,  favorable  to  im- 


106       ANTAGONISM   BETWEEN    REMEDIES    AND   DISEASES. 

provement  in  the  local  state.  The  reduction  of  abnormal  heat  is 
not  less  useful.  Chloral,  therefore,  unquestionably  exerts  a  favor- 
able influence  if  it  does  not  dissolve  an  exudation.  An  important 
contraindication  should  not  be  overlooked — that  is,  the  paralyzing 
effect  of  chloral  on  a  weak  heart.  When  exhibited  for  the  proposed 
treatment  the  dose  should  be  small,  and  not  administered  more  fre- 
quently than  every  two  hours.  The  tendency  to  cardiac  depression 
can  be  overcome  by  the  joint  administration  of  atropia,  which  does 
not  lessen  the  utility  of  the  remedy  for  the  purpose  for  which  it 
is  used. 

That  the  alkalies,  especially  the  potash,  ammonia,  and  lithia 
salts,  by  increasing  the  alkalinity  of  the  blood,  check  exudations, 
and  cause  their  solution,  more  or  less  effectively,  after  they  have 
formed,  seems  a  perfectly  well-established  fact  in  clinical  experi- 
ence. This  mode  of  treating  inflammations  was  made  use  of  on  a 
large  scale  by  the  late  J.  Hughes  Bennett,  whose  exceptional  expe- 
rience on  this  point  entitles  his  declarations  to  special  considera- 
tion. Alkalies  may  be  advantageously  given  in  alternation  with 
chloral.  It  must  be  remembered,  of  course,  that  the  more  alkaline 
the  blood,  the  more  active  is  chloral.  As  ammonia  is  more  diffusi- 
ble than  the  other  alkalies,  it  has  always  seemed  to  me  to  be  more 
effective.  It  is  best  given  in  the  form  of  the  carbonate  dissolved 
in  the  officinal  liquor  ammonii  acetatis.  When  the  exudation  is 
undergoing  solution  preparatory  to  absorption  and  extrusion,  digi- 
talis and  quinia  again  come  into  use.  The  particular  objects  of 
their  use  at  this  time  are  to  give  tone  to  vessels  long  in  a  paretic 
state,  and  to  favor  the  transformation  and  elimination  of  the  in- 
flammatory products.  Digitalis  is  probably  a  more  serviceable 
remedy  to  secure  these  purposes  than  is  quinia.  Besides,  as  a  re- 
sult of  the  more  or  less  long-continued  strain  on  the  heart,  its  action 
is  irritable,  quick,  and  wanting  in  energy — and  these  conditions  are 
removed  by  digitalis. 

The  treatment  of  fever,  or  of  that  complexus  of  morbid  symp- 
toms known  as  fever,  is  a  very  wide  subject.  We  are  now  con- 
cerned with  the  antagonists  of  fever,  but,  taking  this  restricted 
view,  there  is  still  much  to  be  considered — so  much  that  I  must 
needs  confine  myself,  during  the  short  time  at  my  disposal,  to  the 
barest  mention  of  the  chief  points.  The  discussion  of  the  nature 
of  fever  has  been  very  fruitful  in  the  past  few  years,  but  it  has  not 
settled  the  question,  and  we  are  still  in  the  dark  as  to  its  essence. 
The  existence  of  a  heat-regulating  center  is  both  maintained  and 


ANTAGONISTS   TO    FEVEK.  107 

denied.  Is  there  in  fever  increased  production  or  retention  of  beat  ? 
The  greater  formation  and  excretion  of  urea  and  of  carbonic  acid 
indicate  that  the  oxidation  processes  are  accelerated,  and  therefore 
there  must  be  increased  production  of  heat ;  but,  as  the  derange- 
ment involves  also  the  radiation  of  heat  from  the  body,  there  must 
in  fever  be  also  a  less  quantity  of  heat  radiated.  No  single  source 
of  heat  can  therefore  be  alone  concerned  in  the  production  of  fever, 
but  the  truth  probably  lies  to  a  greater  or  less  extent  in  all  the 
theories. 

The  means  for  reducing  fever  heat,  which  we  now  possess,  oper- 
ate by  both  modes — on  the  source  of  heat  production,  and  by  facili- 
tating its  dispersion.  In  the  first  group  are  the  medicines  which- 
stop  or  hinder  those  processes  on  which  the  formation  of  heat  de- 
pends :  they  are  known  as  antipyretics.  Besides  the  antipyretic  med- 
icines proper,  there  are  numerous  remedies,  the  paralyzers  especially,, 
which  diminish  heat  production  among  other  toxic  phenomena. 

The  first  of  the  agents  affecting  heat  production  is  repose — the 
cessation  of  all  activity.  I  was  the  first,  or  among  the  first,  to  show 
that,  if  rabbits,  pigeons,  and  other  small  animals  are  so  fettered  as 
to  be  kept  immovable  for  some  time,  the  temperature  of  their  bodies 
declines.  The  period  of  greatest  depression  in  the  temperature  of 
man  is  in  the  early  morning,  after  the  repose  of  the  night.  Medica- 
ments that  suspend  muscular  activity  cause  a  reduction  of  tempera- 
ture, which  is  quite  independent  of  any  influence  which  they  may 
exert  on  heat  production.  It  is  obvious  that  conclusions  drawn 
from  observations  in  which  this  cause  of  lowered  temperature  is  not 
accounted  for  must  be  defective  and  misleading. 

There  are  numerous  agents  which  affect  heat  production,  the 
most  important  being  quinia,  salicylic  acid,  resorcin,  chloral,  digi- 
talis, aconite,  and  veratrum  viride.  Besides  these,  all  the  remedies 
which  depress  the  functions  of  respiration  and  circulation  more  or 
less  diminish  heat  production.  Unquestionably,  quinia  holds  the 
first  position  as  an  antipyretic.  After  an  exhaustive  examination 
of  the  relative  merits  of  these  agents,  including  cold  baths  and  all 
the  methods  of  hydrotherapy,  Liebermeister  holds  that  quinia  i& 
entitled  to  the  first  place  as  an  antipyretic,  and  that,  if  he  were 
restricted  to  one  agent,  he  would  choose  quinia.  Although  this 
is  the  testimony  of  but  one  clinician,  a  representative  of  the  Ger- 
man school*,  his  opinion  is  but  an  echo  of  the  general  sentiment 
among  the  more  enlightened  medical  thinkers.  The  utility  of 
quinia  consists  in  its  remarkable  power  to  reduce  temperature,  con- 


108       ANTAGONISM   BETWEEN    REMEDIES    AND    DISEASES. 

joined  with  a  minimum  of  evil  effects.  I  have  already,  in  discuss- 
ing its  applications  to  the  treatment  of  inflammation,  entered  some- 
what into  the  nature  of  its  antipyretic  action.  I  need  now  merely 
state  that  the  reduction  of  temperature  effected  by  quinia  is  the  re- 
sult of  its  influence  over  the  vital  activity  of  protoplasm  and  over 
the  so-called  ozonizing  action  of  the  blood.  The  diminution  in  the 
oxidizing  processes  is  shown  in  the  great  reduction  of  urea  forma- 
tion. The  quantity  of  quinia  necessary  to  effect  any  considerable 
reduction  of  temperature  has  been  pretty  closely  ascertained :  not 
less  than  twenty  grains  can  have  any  distinct  antipyretic  effect.  It 
is  true,  in  malarial  diseases  much  smaller  doses  may  diminish  fever, 
but  here  another  element  enters  the  problem.  Our  G-erman  con- 
freres give  twenty,  thirty,  forty,  even  sixty  grains  for  the  anti- 
pyretic effect,  and  repeat  it  as  may  be  necessary,  to  keep  the  tem- 
perature down  at  the  proper  level,  and  withhold  it,  when  the  result 
is  attained,  until  required  again.  The  popular,  and  to  some  small 
extent  the  professional,  opinion,  that  large  doses  of  quinia  affect  the 
ears  unfavorably,  has  no  support  in  my  experience.  I  have  used 
large  doses  with  excellent  results  in  inflammation  of  the  middle  ear. 
That  it  has  any  other  injurious  effect  on  the  human  constitution,  in 
proper  medicinal  doses,  seems  to  me  not  at  all  probable.  That 
quinia  exercises  the  same  curative  influence  over  fevers — typhoid, 
for  example — that  it  does  over  malarial  diseases,  can  not  be  enter- 
tained for  one  moment.  The  effect  it  has  on  the  course  of  fever  is 
•due  to  its  antipyretic  property ;  on  malarial  diseases,  the  action  is 
specific  and  particular.  It  is  effective,  then,  in  the  treatment  of 
fever,  according  to  the  degree  in  which  it  reduces  the  temperature, 
and  the  value  of  this  is  determined  by  the  importance  of  the  febrile 
element  in  the  morbid  complexus. 

Salicylic  acid  has  many  analogies  with  quinia.  Like  quinia,  it 
does  not  affect  the  normal  temperature  to  any  considerable  extent, 
but  has  a  powerful  effect  on  the  temperature  of  fever.  The  first 
demonstration  of  this  fact,  by  Butt,*  has  been  since  confirmed  by 
numerous  observers.  The  quantity  required  to  produce  a  decided 
.antipyretic  effect  is  not  less  than  sixty  grains,  but  eighty,  even  one 
hundred  and  twenty  grains,  are  sometimes  necessary.  Profuse 
diaphoresis  usually  occurs,  and  then  the  decline  of  temperature  be- 
gins, about  a  half  hour  after  the  proper  quantity  has  been  taken. 
The  duration  of  the  decline  is  about  six  hours,  and  this  furnishes 

*  "  Centralbl.  f.  d.  med.  Wissensch.,"  Ixxxii,  1875. 


ANTAGONISTS    TO    FEVEK.  109V 

the  measure  for  its  repetition.  Although  the  first  reports  of  the 
curative  power  of  salicylic  acid  in  malarial  diseases,  in  which  it  was 
ranked  next  to  quinia,  have  not  been  confirmed,  it  still  maintains- 
its  original  position  as  an  antipyretic.  For  the  reduction  of  the 
temperature  in  fevers  it  does  not  have  the  position  of  quinia,  but  in 
acute  rheumatism  its  antipyretic  action,  which  appears  to  be  the 
secret  of  its  curative  power  in  that  disease,  renders  it  highly  use- 
ful. 

A  new  remedy,  resorcin,  is  likely  to  become  useful  as  an  anti- 
pyretic and  as  an  antiseptic.  Originally  obtained  from  a  resin,  and 
because  it  has  some  similarity  to  orcin,  its  name  was  compounded  of 
the  two.  According  to  its  chemical  composition,  resorcin  is  meta- 
dihydroxyl-benzol,  and  is  a  phenol.  It  has  no  irritant  properties, 
and  may  be  injected  subcutaneously  without  danger  of  inflammation 
and  abscess.  The  dose  as  an  antipyretic  is  about  sixty  grains.  It 
produces  at  first  quickened  action  of  the  heart,  flushing  of  the  face, 
and  a  sense  of  warmth  and  precordial  oppression.  Then  perspira- 
tion begins,  and  is  very  profuse.  With  the  appearance  of  perspira- 
tion, the  temperature  declines.  The  antipyretic  effect  on  febrile 
temperature  is  very  decided,  and  hence  resorcin  may  come  into 
general  use  as  an  antipyretic,  the  more  especially  as  it  does  not  pro- 
duce irritation  of  the  parts  to  which  it  is  applied. 

The  effect  of  digitalis  on  febrile  temperature,  although  decided,, 
is  not  equal  to  that  exerted  by  quinia.  It  is  also  much  slower  in 
action.  The  systemic  effects  of  digitalis  require  several  hours  for 
their  development,  and,  unfortunately  for  its  use  in  the  treatment 
of  fevers,  it  causes,  in  any  considerable  quantity,  very  great  gastro- 
intestinal disturbance.  Furthermore,  its  administration  must  be 
regarded  as  ill  advised  in  cases  with  weakness  of  the  heart  from 
granular  degeneration  of  its  muscular  fiber.  The  quantity  required 
to  effect  any  considerable  reduction  of  temperature  is  so  great  as  to 
excite  much  gastric  irritability,  besides  being  hazardous.  When 
employed  as  an  antipyretic,  it  should  be  used  to  aid  the  action  of 
quinia,  rather  than  alone.  Nevertheless,  there  are  symptoms  of  the 
febrile  state  against  which  digitalis  may  be  used  with  signal  advan- 
tage. In  the  exanthematous  fevers,  scarlet  fever  especially,  digi- 
talis antagonizes  the  symptoms  most  active  in  bringing  about  a 
fatal  result,  viz.,  a  weak  heart,  low  arterial  tension,  quick  circula- 
tion, high  temperature,  and  deficient  urinary  secretion.  Digitalis- 
slows  while  it  strengthens  the  heart,  raises  the  tension  of  the  arte- 
rial system,  and  stimulates  the  kidneys  to  renewed  action.  If  there 


110       ANTAGONISM    BETWEEN    REMEDIES    AND   DISEASES. 

be  difficulty  in  retaining  it  by  the  stomach,  the  effects  of  digitalis 
may  be  procured  by  external  application  of  the  moistened  leaves. 

The  antipyretic  effects  of  aconite  are  less  certain  and  decided 
than  those  of  digitalis,  and  it  differs  from  the  latter  in  the  character 
of  its  action.  Aconite  lessens  the  activity  of  the  motor  apparatus 
of  the  heart,  and  lowers  the  arterial  tension,  and  hence  it  opposes 
the  febrile  state  associated  with  rapid,  strong,  and  turbulent  action 
•of  the  heart  and  elevated  arterial  tension.  It  is  against  certain 
symptoms  of  the  febrile  condition  that  aconite  is  useful,  and  not  as 
an  antipyretic.  Whenever  high  fever  is  due  to  sthenic  inflamma- 
tion, it  may  lower  the  fever  by  acting  against  its  source.  The  same 
observations  are  true  of  veratrum  viride.  By  slowing  the  heart  and 
diminishing  the  amount  of  blood  passing  into  the  inflamed  area,  by 
limiting  the  work  done  by  the  lungs,  and  thus  lessening  oxidation 
in  general,  veratrum  viride  has  an  unquestionable  influence  on  the 
inflammatory  process  and  on  the  accompanying  fever,  but  it  has 
not  much  value  as  an  antipyretic  purely. 

The  most  efficient  remedy  against  fevers  of  the  essential  group 
is  cold,  which  acts  on  heat  after  its  production.  Nothing  could  be 
more  exact  than  the  antagonism  of  cold  and  heat.  By  the  applica- 
tion of  cold  to  the  body,  the  heat  is  removed.  The  influence  of  cold 
and  heat,  respectively,  on  the  circulation  is  admirably  shown  in  the 
experiment  on  the  frog's  heart,  to  which  I  have  several  times  alluded. 
"When  the  blood  is  heated  above  the  normal  by  the  fever  process 
the  action  of  the  heart  increases  correspondingly ;  when  the  surface 
blood  is  cooled,  presently  the  whole  amount  of  blood  in  the  body 
has  its  temperature  lowered,  and  the  heart  soon  slows  its  beat. 
Thus,  whether  fever  means  increased  production  of  heat  or  reten- 
tion, the  action  of  cold  is  equally  efficient  in  reducing  it.  The  re- 
sult is  the  same,  whether  cold  is  applied  by  the  cold  bath,  by  the 
-cold  pack,  by  the  rectal  injection  of  ice  water,  or  by  ice  bags.  That 
part  of  the  blood  in  contact  with  the  cold  surface  loses  a  portion  of 
its  heat,  and  thus  gradually  the  whole  mass  of  blood  has  its  tem- 
perature reduced.  With  the  decline  of  the  body  heat  cease  all  those 
changes  due  to  the  elevated  temperature.  How  quickly  high  heat 
may  kill  is  seen  in  heat  fever,  or  sunstroke,  and  in  the  hyperpy- 
rexia  of  some  cases  of  acute  rheumatism.  How  life  may  be  saved 
under  circumstances  of  imminent  danger  is  witnessed  when,  in  the 
condition  of  hyperpyrexia,  the  abnormal  heat  is  removed  by  the  ap- 
plication of  cold.  In  the  two  conditions,  often  confounded  under 

term  sunstroke,  of  heat  fever  and  heat  exhaustion,  we  have  an 


ANTAGONISTS    OF    SPECIFIC    DISEASES.  Ill 

excellent  illustration  of  the  principles  of  antagonism.  In  heat  fever 
the  abnormal  temperature  is  removed  by  the  cold  douche,  the  cold 
bath,  the  cold  wet  pack,  etc.,  agents  which  would  prove  fatal  if  ap- 
plied in  the  case  of  heat  exhaustion,  in  which  the  temperature  is 
rather  below  than  above  normal,  the  heart  feeble,  and  the  respira- 
tion slow  and  shallow.  The  remedies  suited  to  heat  exhaustion — 
brandy  and  tincture  of  opium — would  soon  overcome  the  subject  of 
heat  fever.  The  principle  of  antagonism,  therefore,  is  the  sure 
guide  which  we  must  follow  in  these  dangerous  circumstances. 
Having  explained  the  mechanism  of  the  antagonism,  it  would  serve 
no  useful  purpose  to  enter  into  details  regarding  the  application  of 
cold.  That  the  treatment  of  the  fevers — of  typhoid  especially — has 
been  greatly  advanced  by  the  method  of  hydrotherapy,  seems  hardly 
to  admit  of  question.  The  treatment  by  cold  baths  is  particularly 
adapted  to  those  fevers  in  which  the  temperature  is  the  dominant 
fact,  but  hydrotherapy  becomes  less  and  less  important,  the  more  the 
morbid  complexus  is  determined  by  some  special  poison  acting  on 
particular  organs.  Typhoid  represents  one  group ;  small-pox  the 
other  group  of  febrile  affections. 

The  third  and  last  division  of  maladies  against  which  we  may 
direct  antagonists  is  that  of  the  animal  poisons,  hydrophobia,  syphi- 
lis, the  diatheses,  and  the  cachexias.  This  is  a  most  difficult  sub- 
ject. Woorara,  as  I  have  already  mentioned,  has  in  two  instances 
seemed  to  antagonize  the  convulsive  phenomena  of  hydrophobia. 
To  this  statement  may  be  added  the  singular  case  recently  treated 
by  pilocarpine,  in  which  the  tragic  death  in  a  wild  delirium  maybe 
explained  by  the  accidental  moral  causes,  the  spasms  having  sub- 
sided under  the  action  of  the  remedy.  It  is  not  difficult  to  conceive 
that  the  poison  may  be  eliminated  by  the  profuse  salivary  flow. 
Yery  striking  are  the  results  obtained  by  Dr.  Guttmann*  in  the  treat- 
ment of  diphtheria  with  pilocarpine.  Of  eighty-one  patients  with  this 
disease  so  treated,  not  one  died.  He  assumes  that  the  free  salivary 
discharge  causes  softening  and  detachment  of  the  false  membrane, 
but  there  must  be  some  other  antagonistic  influence  at  work  to  pro- 
duce such  uniformly  good  results.  It  is  very  desirable  to  have  fur- 
ther experience  with  the  effects  of  pilocarpine ;  but  it  should  not  be 
forgotten  that  this  remedy  has  a  depressing  effect  on  the  heart,  and 
may  therefore  coincide  with  the  poison  of  diphtheria,  which  also 
paralyzes  the  heart. 

*  "  Berlin,  klin.  Woeh.,"  1880,  No.  40. 


112       ANTAGONISM   BETWEEN   REMEDIES   AND   DISEASES. 

Probably  no  fact  is  better  established  in  therapeutics  than  the 
curative  effect  of  mercury  in  constitutional  syphilis.  Some  resem- 
blance may  be  admitted  to  exist  in  the  constitutional  effects  of  both 
agents.  They  manifest  a  tendency  to  attack  the  same  tissues,  and 
to  produce  lesions  of  a  parallel,  although  not  of  the  same,  kind. 
They  must  therefore  exert  an  antagonism  at  the  points  of  contact, 
for  no  one  can  pretend,  I  think,  that  the  poison  of  syphilis  and  the 
poison  mercury  are  the  same  or  similar.  They  are  antagonists,  and 
of  such  decided  antipathy  that  they  can  not  exist  together  in  the 
same  organ  or  tissue — one  must  displace  the  other.  The  action  of 
iodide  of  potassium  is  different.  This  is  a  most  diffusible  substance,, 
and  in  a  few  minutes  after  being  taken  has  appeared  in  all  parts  of 
the  organism.  Its  chemical  affinities  are  such  that  mineral  matters 
deposited  in  the  tissues  are  sought  out  and  eliminated  in  combina- 
tion. It  is  therefore  a  chemical  antidote,  rather  than  a  physiologi- 
cal antagonist. 

Reviewing,  then,  the  great  subjects  of  the  inflammations,  fevers, 
and  specific  and  diathetic  maladies,  it  is  perfectly  obvious  that  the 
only  certain  method  of  management  is  the  use  of  the  antagonist 
remedies.  Although  I  did  not  apply  the  principles  to  individual 
examples  of  inflammation,  they  are  equally  applicable  to  all  forms. 

Taking  finally  a  comprehensive  view  of  the  subject,  what  are 
the  lessons  to  be  learned  ?  It  is  obvious,  I  think,  that  the  only  rule 
which  we  apply  in  therapeutics,  so  far  as  any  rule  is  applicable,  is 
the  rule  or  principle  of  antagonism.  As  respects  the  treatment  of 
the  state  induced  by  poisons,  the  antagonism  is  direct.  The  effects 
of  the  two  opposing  agents  counterbalance  each  other,  until  the 
natural  powers  secure  the  elimination  of  the  poison.  When  a  toxic 
substance  enters  the  blood,  a  series  of  disturbances  follows,  due  to 
its  presence,  to  its  action  on  the  tissues  for  which  it  has  a  special 
affinity,  and  to  the  efforts  made  for  its  elimination.  The  antagonist 
pursues  a  similar  course,  but  affects  the  particular  tissue  for  which 
it  has  an  affinity  in  an  opposite  manner,  and  thus  prevents  the  im- 
pairment of  function,  which  would  otherwise  result  in  death,  until 
elimination  occurs.  The  effort  of  the  organism  is  always  against 
the  retention  of  organic  poisons,  and  their  elimination  is  always 
effected  if  there  be  sufficient  time,  and  if  the  organs  concerned  are 
in  a  healthy  state. 

As  respects  diseases  of  particular  organs,  we  find  that  antago- 
nism is  exerted  in  two  modes :  by  similarity,  and  by  direct  antago- 
nism, and  that  the  opposition  takes  place  in  respect  to  the  latter 


MODE    OF   ANTAGONISM.  113 

mode,  at  least,  in  the  symptoms.  The  antagonism  by  similarity  is 
the  action  of  the  remedy  on  the  same  tissue,  and  with  similar  objec- 
tive signs,  but  the  effect  on  the  tissue  is  opposed,  for  the  disturbance 
produced  by  the  remedy  must  necessarily  be  different  in  kind  from 
that  produced  by  the  disease.  Two  actions  of  an  opposed  kind  on 
a  diseased  tissue  must  necessarily  result  in  one  of  two  ways :  either 
the  disease  is  arrested,  and  an  equilibrium  is  restored,  or  one  or  the 
other  action  predominates.  If  a  proper  balance  of  actions  is  ob- 
tained, and  the  disease  is  a  functional  one,  a  cure  must  be  the  result. 
This  is,  in  fact,  an  exemplification  of  the  old  doctrine  of  substitu- 
tion, and  a  scientific  expression  of  its  truth.  In  the  process  by 
direct  antagonism,  the  symptoms  produced  by  the  disease  are  op- 
posed by  the  functional  disturbance  caused  by  the  remedy.  If 
rightly  timed,  and  if  the  disease  be  functional  in  character,  the  op- 
position of  actions  results  in  an  equilibrium,  which  is  health.  If 
the  alterations  of  structure  are  of  a  kind  to  be  removed  by  the  op- 
eration of  physiological  processes,  then  also  may  restoration  be 
effected  by  the  exertion  of  an  antagonism.  In  the  treatment  of 
inflammation  we  have  an  illustration  of  how  the  successive  steps  in 
the  development  of  the  process  are  in  turn  subjected  to  the  action 
of  opposing  agents.  As  this  process  enters  largely  into  the  struct- 
ural alterations  produced  by  disease,  we  are  thus  encouraged  in  our 
efforts  to  obtain  results  by  the  application  of  the  law  of  antago- 
nistic action. 

It  is  obvious  that  treatment  must  be  symptomatic,  but  not  in  the 
ordinary  sense.  To  apply  physiological  antagonists  with  accuracy,  a 
careful  analysis  of  symptoms  must  be  made,  and  we  must  proceed 
from  the  merely  objective  to  the  underlying  state.  Let  us  take,  for 
example,  the  symptom  fever.  How  shall  we  oppose  it  ?  Fever  is 
made  up  of  several  symptoms :  of  increased  action  of  the  heart, 
usually  low  tension  of  the  vessels,  of  higher  temperature,  and  in- 
creased waste.  To  counterbalance  the  symptom  fever,  then,  we 
must  employ  agents  to  lower  the  action  of  the  heart,  to  raise  the 
tension  of  the  arterial  system,  to  depress  the  temperature,  and  to 
stop  waste.  One  or  two  or  more  agents  may  be  required  to  accom- 
plish this  work  in  its  entirety. 

The  right  use  of  remedies  in  accordance  with  the  principle  or 
law  of  antagonism  requires  an  accurate  knowledge  of  physiological 
therapeutics.  To  this  study,  as  a  distinguished  French  therapeutist, 
Behier,  has  lately  said,  the  medical  profession  should  give  its  unre- 
mitting attention.  Is  it  the  case?  Is  there  that  interest  in  the 


114  PHYSIOLOGICAL   VS.    EMPIRICAL   METHOD. 

study  of  modern  therapeutics  which  we  find  exhibited  in  other  de- 
partments of  medical  science  and  art  ?  I  fear  not.  There  is  still 
present  the  notion  that  observation  and  experience  should  be  the 
sole  foundations  for  the  construction  of  a  therapeutical  science. 
The  old  principle,  that  a  remedy  which  has  cured  a  disease  must  cure 
all  analogous  cases,  is  still  the  guiding  principle  with  many  of  the 
practitioners  of  our  day.  Besides  the  numberless  fallacies,  the  prod- 
uct of  individual  experience,  the  observation  of  analogies  is  in 
everyway  misleading.  The  advocates  of  this  empirical  method  are 
fond  of  asserting  that  the  observations  on  animals  can  not  be  applied 
with  any  certainty  to  man  ;  that  rabbits  eat  belladonna  leaves  with 
impunity,  and  that  pigeons  can  hardly  be  poisoned  by  opium  ;  but 
physiological  research  demonstrates  that  by  another  mode  of  admin- 
istration these  animals  are  affected  in  the  same  way  as  man.  While 
decrying  the  results  obtained  by  experimental  study,  by  the  physio- 
logical method,  they  are  hourly  indebted  to  it  for  the  accurate  ap- 
plication of  remedial  agents.  I  might  offer,  for  the  consideration  of 
those  who  pursue  the  empirical  method,  the  declaration  of  Bernard, 
who  affirms  that  observations  on  animals  by  the  physiological  method 
are  perfectly  conclusive  as  to  the  effect  of  these  agents  on  man,  but 
I  prefer  to  remind  them  that  many  of  the  remedies  in  constant  use 
are  those  for  which  they  are  indebted  to  the  physiological  method 
of  research.  Until  Magendie  studied  strychnia,  it  was  merely  the 
mysterious  upas  poison  ;  until  Bernard  examined  woorara,  muscular 
irritability  was  the  dream  of  Haller.  Chloral  continued  a  mere 
chemical  curiosity,  until  the  genius  of  Liebreich  demonstrated  by 
one  effort  its  wonderful  hypnotic  qualities.  The  results  achieved  in 
that  way  have  a  remarkable  permanence.  While  the  notions  of  the 
actions  and  uses  of  drugs  engendered  by  experience  and  observa- 
tion are  constantly  changing,  the  deductions  of  experiment  have 
the  same  value  as  the  same  methods  in  the  other  experimental 
sciences.  To  this  end  we  should  direct  our  best  efforts,  and  rest 
satisfied  with  no  less  certainty  than  that  which  belongs  to  the  exact 
sciences,  until  we  have  attained  to  such  a  degree  of  perfection  that, 
the  disease  being  given,  the  remedy  follows. 


APPENDIX. 


CASES  OF  OPIUM  POISONING. 

THE  fatal  cases  are  not  given  in  this  list,  since  they  have  been  narrated  in 
the  first  lecture. 

No  attempt  has  been  made  to  arrange  the  cases  in  any  given  order,  chrono- 
logical or  otherwise.  Such  facts  and  the  references  are  given  as  will  enable  any 
one  desiring  to  investigate  on  his  own  account  to  identify  the  cases. 

!•  ADAMSON-.  "The  British  Medical  Journal,"  January  6,  1866.  1  oz.  of 
laudanum;  10  drachms  of  tincture  of  belladonna.  Recovery. 

2.  LEGO,  WIOKHAM.     "  Med.  Times  and  Gazette,"  November  3,  1866,  p.  474. 
Chas.  S.,  set.  5.     Egg-cupfnl  of  equal  parts  of  liniment  of  opium  and  liniment  of 
belladonna  (B.  P.),  equivalent  to  5£  grs.  of  belladonna  and  36  minims  of  tinct. 
of  opium.     Recovery. 

3.  PEENTISS,  Dr.  J.  L.     "Chicago  Med.  Journal,"  December,  1866.     Adult. 
6  grs.  of  morphia.     Received  drachm  doses  of  tinct.  of  belladonna  hourl}7"  until 
five  doses  were  taken.     Recovery. 

4.  DEOIN.     uLe  Mouvement  Med.,"  lii,  p.  615,  1867.     Ptisan  of  fresh  bella- 
donna leaves.     Cured  by  tinct.  of  opium. 

5.  PAUL,  CONSTANTS.     "  Bull.  Gen.  de  The'rap.,"  vol.  Ixxiii,  p.  319.     Adult. 
Received  20  grms.  of  laudanum,  and  was  treated  successfully  by  16  grms.  of 
tinct.  of  belladonna. 

6.  HOETON,  Dr.     "Med.  and  Surgical  Reporter,"  Phila.,  June  10,  1876,  p. 
404.     Child,  2!  yrs.     Received  45  grs.  of  extract  of  belladonna.    Four  teaspoon- 
fuls  of  laudanum  were  used  with  success. 

7.  MUEEELL,  Dr.  T.  E.     "  Med.  and  Surg.  Reporter,"  September  30,  1876,  p. 
269.     One  fourth  of  a  grain  of  atropia  taken ;  relieved  by  2  grs.  of  morphia. 

8.  WHAETON,  Dr.  R.  G.     "Phil.  Med.  Times,"  January  22,  1876,  p.  403. 
Poisoning  by  3  grains  of  opium  and  cure  by  ^  gr.  of  atropia. 

9.  SWAYZE,  Dr.  G.  H.  B.     "Phil.  Med.  and  Surg.  Reporter,"  August  12, 
1878.     One  oz.  of  laudanum  taken.     Recovery  under  coffee  and  extract  of  bella- 
donna. 

10.  MOEFIT,  Dr.  CHAS.  M.     "Med.  and  Surg.  Reporter,"  December  15, 1877. 
Poisoning  by  1  oz.  of  laudanum.     Recovery  under  atropia. 


116  APPENDIX. 

11.  WILSON,  Dr.  W.  J.     "Phil.  Med.  Times,"  June  8,  1878.     Poisoning  by 
opium  ai)d  cure  by  atropia. 

12.  Ibid.    Poisoning  by  opium  and  recovery  under  atropia. 

13.  SOHMID,  Dr.     "Schmid's  Jahrbucher,"  vol.  cxxiv,  p.  167.     Atropia  poi- 
soning cured  by  morphia  hypodermatically. 

14.  GBAEFE,  Dr.  VON.     Ibid.,  vol.  clxxv,  p.  356.    Atropia  poisoning  cured 
by  morphia. 

15.  FBONMULLEB,  Dr.     Ibid.,  vol.  cxxvi,  'p.  282.     Atropia  poisoning  cured 
by  morphia. 

16.  COHN,  Dr.  HEEMANN.     "  Berliner  klin.  Wocben.,"  xi,  16,  1865.    Poison- 
ing by  atropia  and  cure  by  morphia. 

IT.  OXLET.  uBrit.  Med.  Journal,"  May  20,  1871.  Child  poisoned  by  the 
liniment  of  belladonna,  equivalent  to  1  drachm  of  belladonna  root.  Cured  by 
44  drops  of  tinct.  of  opium. 

18.  JOHNSTON,  Dr.  CHEISTOPHER.     "Boston  Med.  Journal,"  July  27,  1871. 
Poisoning  by  atropia.     Belief  by  tinct.  of  opium. 

19.  VAN  PETEGHEM.     u  Bull.  Med.  du  Nord,  etc.,"  August,  1870.    Poisoning 
by  atropia  and  cure  by  morphia. 

20.  ALDEN,  Dr.  C.  H.     "  Phil.  Med.  [Times,"  May  15,  1871.    Poisoning  by 
morphia  and  cure  by  atropia. 

21.  MUEDOCH,  Dr.  J.  B.     "N.  Y.  Med.  Kecord,"  October  2, 1871.    Poisoning 
by  tinct.  of  opium  and  cure  by  atropia. 

22.  CASTER,  Dr.  J.  J.     "  Phil.  Med.  Times,"  May  1,  1871.     Man  poisoned  by 
laudanum.    Electricity  and  the  stomach-pump,  and  eleven  injections  of  atropia^ 
ten  being  of  ^  of  a  grain  and  one  of  ^T.     Becovery. 

23.  FINNEY,  Dr.  MAGEE.     "  The  Dublin  Journal,"  July,  1872,  p.  38.    Poison- 
ing by  morphia  and  relief  by  atropia. 

24  to  36  inclusive.  JOHNSON,  Dr.  JAMES.  "  The  Med.  Times  and  Gazette," 
vol.  ii,  1872,  p.  268,  and  vol.  i,  1873,  p.  175.  All  cases  of  opium  or  of  morphia 
poisoning  treated  by  atropia. 

37.  DOBBACHOTOWZ,  Dr.    "  Schmidt's  Jahrbiicher,"  vol.  clxxix,  p.  156.    Poi- 
soning by  morphia ;  relief  by  atropia  and  belladonna. 

38.  COTTEE,  Dr.  S.  K.     "Medical  Times  and  Gazette,"  May  21,  1870.    Poi- 
soning by  a  liniment  composed  of  opium  and  belladonna.     Becovery. 

39.  AGNEW,  Dr.  D.  HATES.     "Penn.  Hospt.  Beports,"  vol.  i,  p.  356.    Poison- 
ing by  atropia ;  cure  by  opium. 

40  and  41.  BADCLIFFE,  Dr.  "  Lancet,"  vol.  ii,  1868,  p.  312.  Two  cases  of 
opium  poisoning  treated  by  belladonna  successfully. 

42.  KUHTE,  Dr.  F.  H.     "Schmidt's  Jahrbucher,"  vol.  clix,  p.  124.    Apothe- 
cary poisoned  by  atropia ;  cured  by  morphia. 

43.  LAMODEID,  JULIUS  J.     "  Phila.  Med.  Times,"  March  16,  1878,  p.  271. 
Woman  poisoned  by  laudanum ;  cured  by  atropia. 

44.  SIEVEKING,  Dr.     "  Med.  Press  and  Circular,"  July  10,  1878,  p.  22.     Case 
of  morphia  poisoning ;  cure  by  atropia. 

45.  HANESEN,  Dr.     "  Wurtlb.  Correspbl.,"  xxxi,  244,  1879.     Child  poisoned 
by  atropia ;  relieved  by  morphia. 

46.  EDDISON,  Dr.     "  Lancet,"  June  14,  1879,  p.  843.    Man  had  6  drachms  of 
laudanum ;  stomach-pump  and  atropia.    Becovery. 


CASES    OF   OPIUM   POISONING.  117 

47  to  55  inclusive.  SEATON,  Mr.  JAMES.  "Med.  Times  and  Gazette,"  vol.  ii, 
1859.  Ten  cases  of  poisoning  by  belladonna  berries — one  fatal. 

56.  LOPEZ,  Dr.  "  North  Amer.  Medico-Chirurg.  Review,"  January,  1860. 
Poisoning  by  opium;  recovery  by  belladonna. 

57 and  58.  LEE,  Dr.  0.  C.  "Amer.  Jour,  of  Med.  Sciences,"  January,  1862, 
p.  57.  One  case  of  opium  and  one  case  of  belladonna  poisoning ;  cured  by  op- 
posite. 

59.  BUREITT,  Dr.  H.  L.  W.     "Med.  and  Surg.  Reporter,"  April  19,  1873,  p. 
316.     Poisoning  by  an  ounce  of  tinct.  of  opium;  recovery  by  an  ounce  of  ext. 
of  belladonna. 

60.  SOHELL,  Dr.  H.  S.     "Phil.  Med.   Times,"  November  29,  1873,  p.  134. 
Opium  poisoning ;  cure  by  atropia. 

61  to  66  inclusive.  WOOD,  Dr.  H.  0.  "  The  Amer.  Jour,  of  Med.  Sci.," 
April,  1873. 

61.  OEOLA8,  Dr.     "  Lyon  M6dicale,"  xix,  1874,  p.  30.    Poisoning  by  atropia ; 
cure  by  opium. 

68.  LENTE,  Dr.  F.  D.     "  N.  Y.  Med.  Record,"  January  1, 1874,  p.  8.    A  case 
illustrating  the  antagonism  of  morphia  and  atropia. 

69.  LAUTIEE,  Dr.     "  Gazette  des  H6pitaux,"  Ixv,  1874,  p.  575.    Poisoning  by 
belladonna ;  cure  by  opium. 

70.  POOLE,  Dr.  S.  W.     "The  Practitioner,"  October,  1874,  p.  251.    Poison- 
ing by  morphia  ;  relief  by  atropia. 

71.  DAVIDSON,  Dr.  FEANK.     "  Med.  Press  and  Circular,"  March  31,  1875,  p. 
267.     Poisoning  by  liniment  of  belladonna ;  cure  by  opium. 

72.  HEDLEE,  Dr.     "Ber.  klin.  Wochen.,"  xxxiv,  1875,  p.  471.    Poisoning  by 
atropia ;  cure  by  morphia. 

73.  HEATON,  Dr.  J.  D.     "  Med.  Times  and  Gazette,"  April  17,  1875,  p.  413. 
Opium  poisoning ;  cure  by  atropia. 

74.  ABEILLE,  Dr.     "  Bull,  de  1'Acad.,"  quoted  by  the  "  Med.  Times  and  Gaz.," 
vol.  ii,  1872,  p.  342.    Poisoning  by  morphia ;  cure  by  atropia. 

75.  WILSON,  Dr.  BENJ.     "The  Med.  and  Surg.  Reporter,"  November  17, 
1868.    A  case  of  poisoning  by  opium ;  cured  by  atropia. 

76.  MoGEE,  Dr.  J.  P.     "  Amer.  Jour,  of  Med.  Sciences,"  January,  1869,  p. 
282.     Poisoning  by  30  grs.  of  crude  opium;  cure  by  atropia. 

77  and  78o  KAVANAGH,  BEEN.  "  Med.  Press  and  Circular,"  August  11, 1869. 
Two  children  poisoned  by  extract  of  belladonna ;  cured  by  laudanum. 

79.  MASON,  Dr.  E.     "Med.  and  Surg.  Reporter,"  October  2,  1869,  p.  284. 
Poisoning  by  laudanum ;  cure  by  extract  of  belladonna. 

80.  LYONS,  Dr.  J.  J.     "New  Orleans  Jour,  of  Med.,"  April,  1869,  p.  292. 
Girl  of  five  received  5  grs.  morphia  for  quinia ;  cure  by  alum  emetic,  ambulation, 
and  tinct.  of  belladonna. 

81.  YOUNG,  Dr.  P.  B.     "Med.  and  Surgical  Reporter"  (ref.  lost).    Poisoning 
by  opium ;  artificial  respiration,  ambulation,  and  belladonna. 

82.  SINIO,  Dr.  BALDOMERO.     "Bull.  Gen.  de  Ther.,"  vol.  Ixxvi,  p.  126.    Poi- 
soning by  infusion  of  belladonna ;  cure  by  laudanum. 

83  to  102.  Cases  tabulated  by  Dr.  NOEEIS  in  "  The  American  Journal  of  the 
Medical  Sciences  "  for  October,  1862,  and  not  included  in  the  above  list. 

103.  NAISMYTH,  J.  GOODAL,  M.  B.     "  The  Journal  of  Anatomy  and  Physiol- 


118  APPENDIX. 

ogy,"  July,  1880,  p.  449.     A  case  of  the  simultaneous  taking  of  5  or  6  drachma 
of  laudanum  and  2  grains  of  atropia.     Recovery  by  the  antagonism. 

104.  JANEWAY,  Dr.  E.  G.     "The  N.  Y.  Med.   Journal,"  November,  1880. 
Poisoning  by  4  grains  of  morphia,  and  cure  by  atropia,  faradism,  and  an  emetic 
of  mustard. 

105.  MUSSEY,  Dr.  W.  H.,  and  BARTHOLOW,  ROBERTS.     Unpublished.     Boy  of 
eight  received  a  mixture  containing  2  grains  of  morphia  and  1£  grains  of  atropia. 
The  antagonism  was  permitted  to  be  exerted  without  interference,  and  recovery 
promptly  ensued. 

During  the  publication  of  the  abstract  of  my  lectures  in  the  "  New  York 
Medical  Record"  I  received  some  valuable  communications,  several  of  them  con- 
taining notes  of  cases  bearing  on  the  subjects  under  consideration. 

A  case  of  opium  poisoning  in  an  inebriate  is  furnished  me  by  Professor  Dab- 
ney,  of  Virginia,  as  showing  the  antagonistic  power  of  atropia  under  unfavora- 
ble circumstances. 

I  am  also  indebted  to  Dr.  McOullough,  of  Steubenville,  Ohio,  for  the  particu- 
lars of  a  case  of  opium  poisoning  in  an  infant,  in  which  belladonna  proved  an- 
tagonistic. 

A  very  interesting  case  of  opium  poisoning  in  an  infant  is  reported  in  the 
"  New  York  Medical  Record "  for  January  8,  1881,  by  Professor  Samuel  0. 
Chew,  M.  D.,  of  Baltimore.  In  this  case  the  principles  sought  to  be  established 
in  these  lectures  received  admirable  illustration  and  support,  and  its  publication 
is,  therefore,  most  opportune. 

OASES    ILLUSTRATING    THE  ANTAGONISM    OF    STRYCHNIA  AND 

CHLORAL. 

1.  Mr.  LYON  VASEY.     "The  London  Lancet,"  May  17,  1873.    A  girl  of  six- 
teen took  Gibson's  vermin-killer,  equivalent  to  a  £  grain  of  strychnia.     A  cure 
was  effected  by  20  grains  of  chloral  subcutaneously. 

2.  Dr.  OGILVIE  WILL.     "  The  Edinburgh  Medical  Journal,"  April,  1875,  p. 
307.     Attempted  suicide  with  4  to  6  grains  of  strychnia ;  cure  by  the  hypoder- 
matic injection  of  30  grains  of  chloral. 

3.  Dr.  CHARTEEIS.     "The  Lancet,"  April  10,  1875.    Poisoning  by  Gibson's 
vermin-killer,  equivalent  to  4  grains  of  strychnia.     An  emetic  of  zinc  sulphate 
and  the  administration  of  chloral  effected  a  cure. 

4.  Dr.  0.  BIVINB.     "The  Phil.  Medical  Times,"  August  14, 1875,  p.  721.     A 
case  of  strychnia  poisoning  in  a  little  girl  treated  by  chloral  and  bromide  of  po- 
tassium with  success. 

NOTE.  Husemann  has  recently  made  a  special  research  on  the  method  of 
Bivine,  as  he  entitles  it,  and  has  pronounced  against  it. 

5.  Dr.  ANGUS  MAODONALD.     "  The  Edinburgh  Medical  Journal,"  April,  1872, 
p.  882.     Poisoning  by  the  officinal  solution  of  strychnia.     The  inhalation  of  chlo- 
roform was  also  practiced,  but  the  cure  was  effected  by  the  administration  of  50> 
grains  of  chloral. 

6.  Dr.  S.  A.  TURNER.     "The  Phil.  Med.  and  Surg.  Reporter,"  June  15,  1872. 
A  Sioux  Indian,  poisoned  by  an  unknown  quuntity  of  strychnia ;  cure  was  ef- 
fected by  large  doses  of  chloral  as  described  in  the  lecture. 


NOTES.  119 

7.  Dr.  H.  G-.  LANDIS.  "  The  Phil.  Med.  Times,"  October  13,  1877.  A  case 
of  strychnia  poisoning  treated  by  ether  inhalations,  bromide  of  potassium,  and 
chloral. 

I  am  favored  by  Dr.  J.  0.  Dunn,  of  Pittsburgh,  with  rthe  details  of  a  case  of 
chloral  poisoning  iri  which  strychnia  was  the  principal  antagonist,  strong  coffee 
and  ammonia  being  also  administered.  As  the  patient  had  taken  a  large  but  un- 
known quantity  of  alcoholic  stimulants,  it  is  difficult  to  estimate  the  precise  share 
in  the  result  of  the  injections  of  strychnia.  As  remarked  in  the  lecture  on  this 
topic,  the  published  examples  of  chloral  poisoning  do  not  supply  the  conditions 
necessary  for  determining  the  value  of  the  antagonist. 

STRYCHNIA  AND  NIOOTIA. 

The  fact  that  Professor  Haughton,  M.  D.,  of  Dublin,  first  brought  forward 
nicotia  as  an  antagonist  to  strychnia  ("Dublin  Quarterly,"  August,  1862)  should 
have  been  stated  more  definitely  in  the  lecture  on  this  topic. 

ATROPIA  AND  PHYSOSTIGMA. 

I  am  reminded  by  Dr.  R.  S.  Wallace,  of  East  Brady,  that  my  statement  in 
regard  to  the  preponderating  action  of  atropia  needs  some  qualification.  Al- 
though the  effects  of  atropia  are  both  more  decided  and  more  persistent  than 
those  of  eserine  on  the  pupil,  yet  when  the  pupil  is  dilated  by  atropia  it  may  be 
contracted  by  eserine.  In  order  to  maintain  the  contraction,  however,  eserine 
must  be  repeatedly  instilled  into  the  eye. 

NITRITE  OF  AMYL  AND  ERGOTIN. 

In  a  paper  devoted  to  the  consideration  of  certain  agents  acting  on  the  intra- 
cranial  circulation,  Max  Schueller  has  demonstrated  the  existence  of  an  antago- 
nism between  nitrite  of  amyl  and  ergotin.  "  When  the  vessels  of  the  ear  and 
the  brain  are  dilated  to  their  utmost  extent  by  nitrite  of  amyl,  a  subcutaneous 
injection  of  about  one  fourth  of  a  grain  of  ergotin  will  still  produce,  in  ten  to 
fifteen  minutes,  a  very  distinct,  permanent  contraction  of  the  previously  relaxed 
vessels,  lasting  several  days,  in  those  of  the  ear.  On  the  side  of  the  severed 
sympathetic  this  contraction  also  takes  place,  although  it  is  of  less  intensity.  If, 
after  a  well-marked  contraction  by  ergotin,  nitrite  of  amyl  is  caused  to  be  in- 
haled, for  even  one  fourth  to  one  half  hour,  no  dilatation  follows ;  nevertheless, 
the  poisonous  effect  of  the  nitrite  of  amyl  is  not  prevented,  although  of  later  oc- 
currence." "  Berliner  klinische  Wochenschrift,"  Nos.  25  and  26,  1873. 


INDEX. 


'A 

Aconite,  65,  78,  83,  104. 

Amyl  nitrite,  82. 

Anaesthetics,  84. 

Antagonism  of  atropia  and  aconite,  65. 

of  atropia  and  bromal  hydrate,  64. 

of  atropia  and  muscaria,  61. 

of  atropia  and  pilocarpin,  56. 

of  atropia  and  physostigma,  49. 

of  atropia  and  phytolacca,  84. 

of  atropia  and  quinia,  64. 

of  chloral  and  atropia,  72. 

of  chloral  and  picrotoxin,  71. 

of  chloral  and  strychnia,  67. 

of  digitalin  and  muscaria,  83. 

of  digitalin  and  saponin,  83. 

of  digitalis  and  aconite,  82. 

of  morphia  and  aconitia,  78. 

of  morphia  and  atropia,  22. 

of  morphia  and  caffeine,  79. 

of  morphia  and  cocaine,  79. 

of  morphia  and  chloroform,  80. 

of  morphia  and  gelsemium,  77. 

of  morphia  and  theine,  79. 

of  morphia  and  veratrum  viride,  74. 

of  opium  and  aconite,  78. 

of  opium  and  belladonna,  22. 

of  opium  and  gelsemium,  77. 

of  opium  and  veratrum  viride,  74. 

of  strychnia  and  aconitin,  81. 

of  strychnia  and  amyl  nitrite,  82. 

.of  strychnia  and  chloroform,  82. 
Antagonists  to  fever,  106. 

to  inflammation,  102. 

to  specific  diseases,  103. 


B 

Belladonna,  14,  22. 
Bromal  hydrate,  64. 

0 

Caffeine,  79. 

Cardiac  remedies  and  diseases,  95. 
Chloral,  67,  71,  72. 
Chloroform,  80,  86.  - 

D 

Digitalin  and  aconitia,  82. 
and  muscaria,  82. 
and  saponin,  83. 

E 

Eserine  and  atropia,  49. 

F 

Fever  antagonists,  106. 


G 


Gelsemium,  77. 
and  opium,  77. 


Intestinal  diseases  and  remedies,  99. 

M 

Mental  states  and  their  antagonists,  94. 
Morphia  and  aconite,  78. 

and  atropia,  22. 

and  caffeine,  79. 

and  cocaine,  79. 

and  chloroform,  80. 

and  gelsemium,  77. 

and  theine,  79. 

and  veratrum  viride,  79. 


122 


ESDEX. 


Opium,  14,  22,  71,  74,  77. 
Opium  and  aconite,  78. 

and  belladonna,  22. 

and  gelsemium,  77. 

and  veratrum  viride,  74. 


Pain  and  the  anodynes,  92. 
Pilocarpin  and  atropia,  56. 
Picrotoxin,  71,  89. 
Physostigma  and  atropia,  49. 

Q 

Quinia,  64. 

Quinia  in  inflammation,  102. 
in  fevers,  104. 

R 

Respiration  diseases  and  antagonists,  98. 


8 

Saponin,  83. 

Spasm  and  the  paralyzers,  88.. 
Strychnia,  17,  67,  81,  82,  86. 
Strychnia  and  aconite,  81. 

and  amyl  nitrite,  82. 

and  chloral,  67. 

and  chloroform,  82. 


Tetanus  and  its  antagonists,  89. 
Theine,  79. 


Veratrum  viride  and  opium,  74. 


Woorara,  17,  88. 


TREATISE 


MATERIA  HEDICA  AND  THERAPEUTICS. 

REVISED  AND  ENLARGED. 

THIRD  EDITION,  WITH  COMPLETE  INDEX  AND  TABLE  OF  CONTENTS. 
BY  ROBERTS  BARTHOLOW,  M.  A.,  M.  D. 

Professor  of  Materia  Medica  and  Therapeutics  in  the  Jefferson  Medical  College  ;  formerly  Profes- 
sor of  the  Theory  and  Practice  of  Medicine,  and  of  Clinical  Medicine,  and  Professor  of  Materia 
Medica  and  Therapeutics  in  the  Medical  College  of  Ohio ;  Physician  to  the  Hospital  of  the  Good 
Samaritan;  Corresponding  Member  of  the  New  York  Neurological  Society,  etc. 

In  one  volume,  8vo.    563  pages.    Cloth,  $5.00;  sheep,  $6.00. 


The  work  of  Dr.  Bartholow  has  commanded  to  an  unusual  degree  the  favor 
of  the  medical  profession.  Three  editions  were  printed  from  the  plates  in  the 
first  year.  In  the  new  and  revised  edition  a  great  many  additions  to  the  text 
have  been  made  at  various  points,  and  a  number  of  new  articles  have  been  in- 
serted. Although  the  work  is  comprised  within  six  hundred  pages,  it  will  be 
found  that  it  embraces  everything  of  importance.  Obsolete  theories  and  chemi- 
cal and  botanical  details,  properly  in  the  domain  of  pharmacy,  have  no  place  in 
this  practical  treatise.  No  details  of  any  value  to  the  physician  are  omitted. 

One  of  the  most  important  innovations  on  existing  methods  in  the  depart- 
ment of  raateria  medica  made  in  Dr.  Bartholow 's  treatise  is  his  chapter  on 
Alimentation.  The  introduction  of  this  subject,  and  its  skillful  handling,  have 
been  especially  commended  by  the  critics  and  by  medical  readers  generally. 
That  no  subject  has  failed  to  receive  adequate  attention  is  evident  enough  on 
perusal  of  the  Table  of  Contents,  which  will  be  sent  to  any  address  upon  appli- 
cation. 

"  Dr.  Bartholow  does  not  misjudge  his  position  in  using  it.  He  is  well  known 
as  a  zealous  student  of  medical  science,  an  acute  observer,  a  good  writer,  a  skilled 
practitioner,  and  an  ingenious,  bold,  though  sometimes  reckless,  investigator. 
His  present  book  will  receive  the  cordial  welcome  which  it  deserves,  and  which 
the  honorable  position  that  he  has  won  entitles  him  to  demand  for  it.  ...  Dr. 
Bartholow's  treatise  has  the  merit — and  a  great  merit  it  is — of  including  diet  as 
well  as  drugs.  .  .  .  His  work  does  not  ignore  or  depreciate  the  value  of  the  em- 
pirical facts  of  a  well-grounded  and  rational  professional  experience,  but,  as  far 
as  possible,  it  bases  the  therapeutical  action  of  remedies  upon  their  physiological 
behavior." — American  Journal  of  the  Medical  Sciences. 

"  Dr.  Bartholow  has  evidently  sought,  in  the  volume  before  us,  to  present  a 
concise,  practical  work — good  for  the  student  as  a  text-book  and  useful  to  the 
practitioner — and  he  has  succeeded  admirably.  He  avoid?,  on  the  one  hand,  the 
unnecessary  detail  of  the  so-called  '  physiological  action  '  of  remedies,  which  ren- 
ders the  reading  of  the  work  of  Dr.  H.  C.  Wood  laborious;  on  the  other  hand, 
he  avoids  the  minutiae  of  Dr.  Stille's  excellent  volumes.  .  .  .  The  book  is  never- ., 
theless  the  .best  one  for  general  use  known  to  us  in  America.  Were  we  now 
about  to  buy  a  work  on  Therapeutics,  etc.,  we  should  select  this  one." — Virginia 
Medical  Monthly. 

D.   APPLETON  &  CO.,  Publishers, 

1,  3,  &  5  Bond  Street,  New  York. 


A  Treatise  on  the  Practice  of  Medicine, 

FOR  THE 

USE  OF  STUDENTS  AND  PKACTITIONEKS. 

SECOND  EDITION,   REVISED  AND  ENLARGED. 
By  BOBEBTS  BABTHOLOW,  M.A.,  M.D.,  LL.D., 

Professor  of  Materia  Medica  and  General  Therapeutics  in  the  Jefferson  Medical  College  of  Phila- 
delphia; recently  Professor  of  the  Practice  of  Medicine  and  of  Clinical  Medicine  in 
the  Medical  College  of  Ohio,  in  Cincinnati,  etc.,  etc. 

In  one  volume,  8vo.    853  pages.    Cloth,  $5.00 ;  sheep,  $6.00. 


The  same  qualities  and  characteristics  which  have  rendered  the 
author's  "  Treatise  on  Materia  Medica  and  Therapeutics "  so  accept- 
able are  equally  manifest  in  this.  It  is  clear,  condensed,  and  accurate. 
The  whole  work  is  brought  up  on  a  level  with,  and  incorporates,  the 
latest  acquisitions  of  medical  science,  and  may  be  depended  on  to  con- 
tain the  most  recent  information  up  to  the  date  of  publicati9n. 

"  In  perusing  the  work,  the  reader  can  not  fail  to  be  struck  with  the  appre- 
ciation on  the  part  of  the  author  of  the  wants  of  the  practitioner.  This  is  ap- 
parent not  only  in  referring  to  the  pathology  and  treatment  of  the  disease,  but 
more  particularly  to  its  symptomatology,  giving  a  pathological  reason  for  the 
latter  which  serves  to  £x  it  in  the  mind  of  the  reader.  The  diagnosis  of  disease 
is  studied  with  particular  care,  and  no  little  pains  are  taken  to  present  in  the 
smallest  space  the  necessary  points  to  be  taken  into  consideration  in  arriving 
at  a  conclusion." — Medical  Record. 

"It  may  be  said  of  so  small  a  book  on  so  large  a  subject,  that  it  can  be  only 
a  sort  of  compendium  or  vade  mecum.  But  this  criticism  will  not  be  just.  For, 
while  the  author  is  master  in  the  art  of  condensation,  it  will  be  found  that  no 
essential  points  have  been  omitted.  Mention  is  made  at  least  of  every  unequivo- 
cal symptom  in  the  narration  of  the  signs  of  disease,  and  characteristic  symptoms 
are  held  well  up  in  the  foreground  in  every  case." — Cincinnati  Lancet  and  Clinic. 

"Probably  the  crowning  feature  of  the  work  before  us,  and  that  which  will 
make  it  a  favorite  with  practitioners  of  medicine,  is  its  admirable  teaching  on  the 
treatment  of  disease.  Dr.  Bartholow  has  no  sympathy  with  the  modern  school  of 
therapeutical  nihilists,  but  possesses  a  wholesome  belief  in  the  value  and  efficacy 
of  remedies.  He  does  not  fail  to  indicate,  however,  that  the  power  of  remedies 
is  limited,  that  specifics  are  few  indeed,  and  that  routine  and  reckless  medication 
is  dangerous.  But  throughout  the  entire  treatise  in  connection  with  each  malady 
are  laid  down  well-defined  methods  and  true  principles  of  treatment.  It  may  be 
said  with  justice  that  this  part  of  the  work  rests  upon,  thoroughly  scientific  and 
practical  principles  of  therapeutics,  and  is  executed  in  a  masterly  manner.  No 
work  on  the  practice  of  medicine  with  which  we  are  acquainted  will  guide  the 
practitioner  in  all  the  details  of  treatment  so  well  as  the  one  of  which  we  are 
writing." — American  Practitioner. 

"The  definitions  are  clear  and  comprehensible;  the  descriptions  are  graphic; 
the  technology  not  too  abstruse ;  the  directions  for  treatment  are  plain  and  prac- 
tical, and  eminently  rational.  The  language  of  Professor  Bartholow  is  succinct 
and  goes  straight  to  the  point.  On  account  of  the  clearness  and  conciseness  of 
this  work,  we  have  no  doubt  that  it  will  at  once  take  a  leading  place  among  the 
classical  treatises  upon  the  practice  of  medicine ;  as  there  has  existed  for  some 
time  a  great  want  for  a  new  Practice  by  an  American  author,  a  hiatus  which 
Bartholow's  Practice  admirably  fills." — College  and  Clinical  Record. 

D.  APPLETON  &  CO.,  Publishers, 

1,  3,  &  5  Bond  Street,  New  York. 


A  PRACTICAL  TREATISE 


Tumors  of  the  Mammary  Gland: 

EMBRACING 

THEIR  HISTOLOGY,  PATHOLOGY,  DIAGNOSIS,  AND 
TREATMENT. 

By  SAMUEL  W.  GROSS,  A,  M.,  M.  D., 

Surgeon  to,  and  Lecturer  on  Clinical  Surgery  in,  the  Jefferson  Medical  College  Hospital  and  the 
Philadelphia  Hospital,  etc. 

In  one  handsome  8vo  vol.  of  246  pages,  with.  29  Illustrations.  Cloth,  price,  $2.50. 


"  We  know  of  no  book  in  the  English  language  which  attempts  to  cover  the 
ground  covered  by  this  one — indeed,  the  author  seems  to  be  the  first  who  has 
sought  to  handle  the  whole  subject  of  mammary  tumors  in  one  systematic  trea- 
tise. How  he  has  succeeded  will  best  be  seen  by  a  study  of  the  book  itself.  In 
the  early  chapters  the  classification  and  relative  frequency  of  the  various  tumors, 
their  evolution  and  transformations,  and  their  etiology,  are  dealt  with;  then 
each  class  is  studied  in  a  separate  chapter,  in  which  the  result  of  the  author's- 
work  is  compared  with  that  of  others,  and  the  general  conclusions  are  drawn 
which  give  to  the  book  its  great  practical  value  ;  finally,  a  chapter  is  devoted  to 
diagnosis,  one  to  treatment,  and  one  to  the  tumors  in  the  mammary  gland  of  the 
male." — New  York  Medical  Journal. 

u  Dr.  Gross  has  produced  a  work  of  real  and  permanent  value ;  it  is  not  over- 
stating the  truth  to  say  that  this  little  volume  is  probably  the  best  contribution 
to  medical  science  which  the  present  year  has  brought  forth.  "We  believe  that 
the  author  has  done  what  he  has  set  out  to  do,  viz.,  constructed  a  systematic 
and  strictly  accurate  treatise  on  mammary  tumors,  and  brought  to  his  task  all 
the  light  afforded  by  the  most  recent  investigations  into  their  pathology." — St. 
Louis  Clinical  Record. 

"  This  book  is  a  real  contribution  to  our  professional  literature ;  and  it  comes 
from  a  source  which  commands  our  respect.  The  plan  is  very  systematic  and 
complete,  and  the  student  or  practitioner  alike  will  find  exactly  the  information 
he  seeks  upon  any  of  the  diseases  which  are  incident  to  the  mammary  gland." 
— Obstetrical  Gazette. 

"  The  work  is  at  once  original,  scientific,  and  practical.  Its  histology  will 
receive  the  careful  attention  of  the  specialists ;  the  surgeon  will  find  it  a  guide 
and  help ;  while  the  general  practitioner,  who  would  be  informed,  and  desires 
to  know  what  will  be  taught  in  our  text-books  and  in  our  colleges,  must  study 
it.  It  is  an  effort  that  will  add  new  honor  to  an  honorable  name,  and  of  which 
we,  as  Americans,  may  all  be  proud  as  an  example  of  original  work  and  investi- 
gation."— Buffalo  Medical  and  Surgical  Journal. 

"  Dr.  Gross  has  given  to  the  profession,  in  his  '  Treatise  on  Tumors  of  the 
Mammary  Gland,'  one  of  the  most  useful  and  original  surgical  works  of  the  nine- 
teenth century.  It  is  but  honest  and  just  praise  to  say  that  in  this  treatise  the 
author  shows  himself  the  intellectual  peer  of  his  great  father,  America's  great 
surgeon." — Louisville  Medical  News. 

D.  APPLETON  &  CO.,  Publishers, 

1,  3,  &  5  Bond  Street,  New  York. 


ON    THE 


Bile,  Jaundice,  and  Bilious  Diseases 


J.  WICKHAM  LEGG,  M.  D.,  F.  R.  C.  S., 

Assistant  Physician  to  St.  Bartholomew's  Hospital,  and  Lecturer  on  Pathological  Anatomy  in  the 

Medical  School. 


In  one  volume,  8vo,  719  pages.    With.  Illustrations  in  Chromo-lithography. 
Price,  cloth,  $6.00 ;  sheep,  $7.00. 


".  .  .'The  book  is  an  exceedingly  good  one,  and,  in  some  points,  we  doubt 
if  it  could  be  made  better.  .  .  .  And  we  venture  to  say,  after  an  attentive  peru- 
sal of  the  whole,  that  any  one  who  takes  it  in  hand  will  derive  from  it  both 
information  and  pleasure;  it  gives  such  ample  evidence  of  honest  hard  work,  of 
wide  reading,  and  an  impartial  attempt  to  state  the  case  of  jaundice,  as  it  is 
known  by  observation  up  to  the  present  date.  .  .  .  The  book  will  not  only  live, 
but  be  in  the  enjoyment  of  a  vigorous  existence  long  after  some  of  the  more 
popular  productions  of  the  present  age  are  buried,  past  all  hope  of  resurrection." 
— London  Medical  Record. 

"...  It  seems  to  us  an  exhaustive  epitome  of  all  that  is  known  on  the 
-subject." — Philadelphia  Medical  Times. 

"  This  volume  is  one  which  will  command  professional  respect  and  attention. 
It  is,  perhaps,  the  most  comprehensive  and  exhaustive  treatise  upon  the  subject 
treated  ever  published  in  the  English  language." — Maryland  Medical  Journal. 

"...  His  book  is,  probably,  the  most  complete  consideration  of  the  whole 
subject,  in  its  details,  in  the  language." — Michigan  Medical  News. 

"...  The  reader  is  at  once  struck  with  the  immense  amount  of  research 
exhibited,  the  author  having  left  unimproved  no  accessible  source  of  information 
connected  with  his  subject.  It  is,  indeed,  a  valuable  book,  and  the  best  store- 
house of  knowledge  in  its  department  that  we  know  of." — Pacific  Medical  and 
Surgical  Journal. 

D.   APPLETON  &  CO.,  Publishers, 

1,  3,  &  5  Bond  Street,  New  York. 


Syphilis  and  Marriage. 

Lectures  delivered  at  the  St.  Louis  Hospital,  Paris. 
By  ALFRED   FOURNIER, 

Professeur  a  la  Facnlte"  de  Medecine  de  Paris;  Medicin  de  THSpital  Saint-Louis;  Membre  de 

I1  Academic  de  MSdecine. 

Translated  "by  P.  ALBERT  MORROW,  M.  D., 

Physician  to  the  Skin  and  Venereal  Department,  New  York  Dispensary ;  Member  New  York 
Dermatological  Society  ;  Member  New  York  Academy  of  Medicine. 

1  wl,  8vo.    Cloth,  $2.00 ;  Sheep,  $3.00. 


NOTICES   OF   THE  PRESS. 

"  In  order  to  write  such  a  work,  not  only  is  a  thorough  knowledge  of  the  subject 
requisite,  but  also  a  firmness  of  hand  and  a  delicacy  of  feeling,  permitting  one  to  treat  of 
the  most  intimate  questions  of  family  life,  without  danger  of  dwelling  upon  unimportant 
histories,  or  of  engaging  in  generalities  and  scientific  discussions,  while  failing  to  set  forth 
the  difficulties  to  be  met  with  in  practice.  Professor  Fournier  has  not,  perhaps,  as  he 
himself  says,  resolved  '  all  the  difficult,  delicate,  perilous  problems  which  affect  the  dear- 
est interests  of  families  and  involve  the  heaviest  responsibility  for  the  physician.'  But 
he  has  stated  and  discussed  them  in  such  a  manner  that  the  physician  who  shall  have 
studied  this  volume  will  be  able  to  direct  his  steps  in  the  midst  of  all  these  dangers.  .  .  . 
We  can  give  only  a  very  incomplete  idea  of  this  work  of  M.  Fournier,  which,  by  its  pre- 
cision, its  clearness,  by  the  forcible  manner  in  which  the  facts  are  grouped  and  presented, 
defies  all  analysis.  'Syphilis  and  Marriage'  ought  to  be  read  by  all  physicians,  who  will 
find  in  it,  first  of  all,  science,  but  who  will  also  find  in  it,  during  the  hours  they  devote  to 
its  perusal,  a  charming  literary  pleasure." — Annales  de  Dermatologie  et  de  Syphiligraphie. 

"...  The  great  merit  of  M.  Fournier  is  to  leave  none  of  the  dangers  introduced  by 
syphilis  into  marriage  in  the  shade — to  throw  upon  their  diverse  and  always  grave  conse- 
quences an  illumination  as  bright  as  it  is  beneficent.  Thus,  one  would  readily  believe 
that  all  is  said  when  he  has  indicated  the  injury  which  the  syphilitic,  in  marrying,  may 
create  for  his  wife  or  for  his  children  ;  when,  for  the  first,  he  has  shown  the  disease  threat- 
ening her  from  direct  or  indirect  contagion ;  when,  for  the  children,  he  has  shown  them 
menaced,  it  may  be  by  the  paternal  procreative  influence,  it  may  be  by  the  action  of  the 
mother  infected  before  or  after  conception  ;  when,  in  fine,  he  has  detailed,  with  the  most  in- 
structive examples  in  support,  the  diverse  effects  of  these  causes  upon  the  life  or  the  health 
of  the  child,  from  inaptitude  for  life  and  native  degenerations  of  the  germ  (subjects  origi- 
nally and  masterly  treated)  to  maladies  or  morbid  predispositions,  which,  at  such  or  such 
period  of  its  development,  the  being  procreated  will  have  to  undergo  by  virtue  of  its  in- 
fected parentage.  .  .  .  After  devoting  eighty  pages  to  the  development  of  this  subject,  one 
would  think  that  the  author  had  exhausted  it.  Not  so.  By  an  ingenious  return,  show- 
ing the  practical  analyst  and  the  honest  man,  he  unveils  an  unexplored  aspect  of  the  sub- 
ject. .  .  .  Written  with  a  perfect  fairness,  with  a  superior  ability,  and  in  a  style  which, 
without  aiming  at  effect,  engages,  interests,  persuades,  this  work  is  one  of  those  which 
ought  to  be  immediately  placed  in  the  hands  of  every  physician  who  desires  not  only  to 
cure  his  patients,  but  to  understand  and  fulfill  his  duty  as  an  honest  man.  .  .  ." — Lyon 
Msdicale. 

D.    APPLETON    &   CO.,  Publishers, 

1,  3,  &  6  BOND  STREET,  NEW  YORK. 


THE 


Popular  Science  Monthly 

Conducted  by  E.  L.  &  W.  J.  YOUMANS. 


THE  POPULAR  SCIENCE  MONTHLY  has  been  often  pronounced  by  first-rate  judges  "  the 
best  periodical  in  the  world."  This  is  because  it  represents  the  most  valuable  thought 
from  the  most  advanced  scientific  men  of  the  age  in  all  countries. 

Its  articles  and  abstracts  of  articles,  original,  selected,  and  illustrated,  give  accounts 
of  all  important  discoveries  and  applications  of  science  that  are  of  general  interest. 

*  Its  pages  will  also  be  found  faithfully  to  represent  the  progress  of  scientific  ideas,  as 
it  affects  the  higher  questions  of  human  interest,  such  as  those  of  the  statesman,  the 
philanthropist,  the  jurist,  the  financier,  the  educator,  the  divine,  the  artist,  the  historian, 
and  the  social  reformer. 

Prominent  attention  has  been  given  and  will  be  given  in  these  pages  to  the  various 
sciences  which  help  to  a  better  understanding  of  the  nature  of  man,  as  affecting  all  pri- 
vate, domestic,  and  public  relations — in  short,  to  the  comprehensive  science  of  human 
nature. 

WHAT   IS  SAID   OF  IT. 

"  This  is  one  of  the  very  best  periodicals  of  its  kind  published  in  the  world.  Its  corps, 
of  contributors  comprise  many  of  the  ablest  minds  known  to  science  and  literature." — 
American  Medical  Journal,  St.  Louis. 

"  It  places  before  American  readers  what  the  ablest  men  of  science  throughout  the 
world  write  about  their  meditations,  speculations,  and  discoveries." — Providence  Journal. 

"  Outside  of  medical  journals,  there  is  no  periodical  published  in  America  as  well 
worthy  of  being  placed  upon  the  physician's  library-table  and  regularly  read  by  him  as 
THE  POPULAR  SCIENCE  MONTHLY." — St.  Louis  Clinical  Record. 

"Not  the  less  entertaining  because  it  is  instructive." — Philadelphia  Age. 

"  A  journal  of  eminent  value  to  the  cause  of  popular  education  in  this  country." — 
New  York  Tribune. 

"  THE  POPULAR  SCIENCE  MONTHLY  is  indispensable  to  every  physician  who  is  desirous 
of  keeping  pace  with  the  advance  in  the  collateral  sciences." — American  Homoeopath. 

"  More  and  more,  year  by  year,  is  this  journal  making  for  itself  a  place  among  the 
absolute  necessities  in  the  estimation  of  scientific  readers  and  workers.  Every  physician 
recognizes  the  imperative  demand  that,  in  order  to  keep  himself  in  line  for  efficient  and 
successful  professional  work,  he  shall  take  and  read  one  or  more  professional  journals. 
Next  after  his  chosen  medical  journals  comes  THE  POPULAR  SCIENCE  MONTHLY  with  its 
rich  store  of  valuable  papers  upon  all  forms  of  kindred  scientific  subjects." — Courier  of 
Medicine.  

The  volumes  begin  in  May  and  November  of  each  year.  Subscriptions  may  begin  at 
any  time.  TERMS  :  $5.00  per  annum  ;  single  number,  50  cents. 

A  club  of  five  will  be  sent  as  directed  for  $20.00  per  annum. 

THE  POPULAR  SCIENCE  MONTHLY  and  NEW  YORK  MEDICAL  JOURNAL,  to  one  address, 
$8.00  per  annum.  Full  price,  $9.00. 

D.  APPLETON  &  CO.,  Publishers, 

1,  3,  &  5  Bond  Street,  New  YorJc. 


MEDICAL  AND  HYGIENIC  WORKS 

PUBLISHED  BY 

D.  APPLETON  &  CO.,  1,  3,  &  5  Bond  St.,  New  York. 


PBICX 

ALCOHOL:  ITS  USE  AND  ABUSE.    Health  Primers.    16mo 01.,  $0  40 

ANSTIE  (FRANCIS  E.)  Neuralgia,  and  Diseases  which  resemble  it.  By 
Francis  E.  Ainstie,  M.  D.,  F.  R.  C.  P.,  Senior  Assistant  Physician  to 
"Westminster  Hospital;  Lecturer  on  Materia  Medica  in  Westminster 
Hospital  School ;  and  Physician  to  the  Belgrave  Hospital  for  Chil- 
dren ;  editor  of  a  The  Practitioner  "  (London),  etc.  12mo.  Cloth,  2  50* 

BARKER  (FORDYCE).  On  Sea-Sickness.  A  Popular  Treatise  for 
Travelers  and  the  General  Reader.  By  Fordyce  Barker,  M.  D., 
Clinical  Professor  of  Midwifery  and  Diseases  of  Women  in  the 
Bellevue  Hospital  Medical  College,  etc.  Small  12mo Cloth,  75 

On  Puerperal  Disease.  Clinical  Lectures  delivered  at  Bellevue 

Hospital.  A  Course  of  Lectures  valuable  alike  to  the  Student  and 

the  Practitioner.  Third  edition.  8vo Cloth,'$5.00* ;  Sheep,  6  00* 

BARNES  (ROBERT).  Lectures  on  Obstetric  Operations,  including  the 
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